25366930 2014 11 4 2014 11 5

1557-7716 2014 Nov 3 Antioxid. Redox Signal. The implication of cancer progenitor cells and the role of epigenetics in the development of novel therapeutic strategies for chronic myeloid leukemia. Significance: Chronic myeloid leukemia (CML) involves the malignant transformation of hematopoietic stem cells, defined largely by the Philadelphia chromosome and expression of the BCR-ABL oncoprotein. Pharmacological tyrosine kinase inhibitors (TKIs) including imatinib mesylate, have overcome limitations in conventional treatment for the improved clinical management of CML. Recent Studies: Accumulated evidence has led to the identification of a subpopulation of quiescent leukemia progenitor cells with stem-like self renewal properties that may initiate leukemogenesis, are also shown to be present in residual disease due to their insensitivity to tyrosine kinase inhibition. Critical issues: The characterisation of quiescent leukemia progenitor cells as a unique cell population in CML pathogenesis has become critical with the complete elucidation of mechanisms involved in their survival independent of BCR-ABL important in the development of novel anticancer strategies. Understanding of these functional pathways in CML progenitor cells will allow for their selective therapeutic targeting. In addition, disease pathogenesis and drug responsiveness is also thought to be modulated by epigenetic regulatory mechanisms such as DNA methylation, histone acetylation and microRNA expression, with a capacity to control CML-associated gene transcription. Future Directions: A number of compounds in combination with tyrosine kinase inhibitors are under preclinical and clinical investigation to assess their synergistic potential in targeting leukemic progenitor cells and/or the epigenome in CML. Despite the collective promise, further research is required in order to refine understanding, and ultimately advance antileukemic therapeutic strategies. Tortorella Stephanie M SM Melbourne, Australia ; stephanie.tortorella@bakeridi.edu.au. Hung Andrew A Karagiannis Tom T ENG JOURNAL ARTICLE 2014 11 3

Antioxid Redox Signal 100888899 1523-0864 2014 11 5 6 0 2014 11 5 6 0 2014 11 5 6 0 aheadofprint 10.1089/ars.2014.6096 25366930 25340776 2014 10 24

1553-7358 10 10 2014 Oct PLoS Comput. Biol. Regression analysis of combined gene expression regulation in acute myeloid leukemia. e1003908 10.1371/journal.pcbi.1003908 Gene expression is a combinatorial function of genetic/epigenetic factors such as copy number variation (CNV), DNA methylation (DM), transcription factors (TF) occupancy, and microRNA (miRNA) post-transcriptional regulation. At the maturity of microarray/sequencing technologies, large amounts of data measuring the genome-wide signals of those factors became available from Encyclopedia of DNA Elements (ENCODE) and The Cancer Genome Atlas (TCGA). However, there is a lack of an integrative model to take full advantage of these rich yet heterogeneous data. To this end, we developed RACER (Regression Analysis of Combined Expression Regulation), which fits the mRNA expression as response using as explanatory variables, the TF data from ENCODE, and CNV, DM, miRNA expression signals from TCGA. Briefly, RACER first infers the sample-specific regulatory activities by TFs and miRNAs, which are then used as inputs to infer specific TF/miRNA-gene interactions. Such a two-stage regression framework circumvents a common difficulty in integrating ENCODE data measured in generic cell-line with the sample-specific TCGA measurements. As a case study, we integrated Acute Myeloid Leukemia (AML) data from TCGA and the related TF binding data measured in K562 from ENCODE. As a proof-of-concept, we first verified our model formalism by 10-fold cross-validation on predicting gene expression. We next evaluated RACER on recovering known regulatory interactions, and demonstrated its superior statistical power over existing methods in detecting known miRNA/TF targets. Additionally, we developed a feature selection procedure, which identified 18 regulators, whose activities clustered consistently with cytogenetic risk groups. One of the selected regulators is miR-548p, whose inferred targets were significantly enriched for leukemia-related pathway, implicating its novel role in AML pathogenesis. Moreover, survival analysis using the inferred activities identified C-Fos as a potential AML prognostic marker. Together, we provided a novel framework that successfully integrated the TCGA and ENCODE data in revealing AML-specific regulatory program at global level. Li Yue Y Department of Computer Science, University of Toronto, Toronto, Canada; The Donnelly Centre, University of Toronto, Toronto, Canada. Liang Minggao M Department of Molecular Genetics, University of Toronto, Toronto, Canada. Zhang Zhaolei Z Department of Computer Science, University of Toronto, Toronto, Canada; The Donnelly Centre, University of Toronto, Toronto, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Canada; Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada. eng Journal Article 2014 10 23

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1750-192X 6 4 2014 Aug Epigenomics Epigenetic modifications in prostate cancer. 415-26 10.2217/epi.14.34 Prostate cancer is the most common cancer in men and the second leading cause of cancer deaths in men in France. Apart from the genetic alterations in prostate cancer, epigenetics modifications are involved in the development and progression of this disease. Epigenetic events are the main cause in gene regulation and the three most epigenetic mechanisms studied include DNA methylation, histone modifications and microRNA expression. In this review, we summarized epigenetic mechanisms in prostate cancer. Epigenetic drugs that inhibit DNA methylation, histone methylation and histone acetylation might be able to reactivate silenced gene expression in prostate cancer. However, further understanding of interactions of these enzymes and their effects on transcription regulation in prostate cancer is needed and has become a priority in biomedical research. In this study, we summed up epigenetic changes with emphasis on pharmacologic epigenetic target agents. Ngollo Marjolaine M Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri Dunant, BP 38, 63001 Clermont-Ferrand, France. Dagdemir Aslihan A Karsli-Ceppioglu Seher S Judes Gaelle G Pajon Amaury A Penault-Llorca Frederique F Boiteux Jean-Paul JP Bignon Yves-Jean YJ Guy Laurent L Bernard-Gallon Dominique J DJ eng Journal Article

England Epigenomics 101519720 1750-192X IM DNA methylation epigenetic modifications histone methylation microRNA prostate cancer 2014 10 22 6 0 2014 10 22 6 0 2014 10 22 6 0 ppublish 10.2217/epi.14.34 25333850 25333344 2014 10 30 2014 10 30

1532-1827 2014 Oct 21 Br. J. Cancer Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3. 10.1038/bjc.2014.540 Background:The pro-inflammatory cytokine interleukin-6 (IL6) promotes colorectal cancer (CRC) development. It is also known to regulate cytochrome P450 (CYP450) enzymes, which are involved in CRC tumour initiation and promotion via activation of chemical carcinogens. Here, IL6 regulation of CYP450 expression was investigated in CRC.Methods:The effect of IL6 on CYP 1A1, 1B1 and 2E1 expression was determined in vitro using CRC cell lines HCT116 and SW480, and CYP450 expression was determined by immunohistochemistry in CRC tissues previously shown to have increased levels of IL6.Results:In mechanistic studies, IL6 treatment significantly induced CYP1B1 and CYP2E1, but not CYP1A1, gene expression in HCT116 and SW480 cells. CYP2E1 expression regulation occurred via a transcriptional mechanism involving STAT3. For CYP1B1 regulation, IL6 downregulated the CYP1B1-targeting microRNA miR27b through a mechanism involving DNA methylation. In clinical samples, the expression of CYP1B1 and CYP2E1, but not CYP1A1, was significantly increased in malignant tissue overexpressing IL6 compared with matched adjacent normal tissue.Conclusions:Colonic inflammation with the presence of IL6 associated with neoplastic tissue can alter metabolic competency of epithelial cells by manipulating CYP2E1 and CYP1B1 expression through transcriptional and epigenetic mechanisms. This can lead to increased activation of dietary carcinogens and DNA damage, thus promoting colorectal carcinogenesis.British Journal of Cancer advance online publication, 21 October 2014; doi:10.1038/bjc.2014.540 www.bjcancer.com. Patel S A A SA Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. Bhambra U U Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. Charalambous M P MP Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. David R M RM Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. Edwards R J RJ Experimental Medicine and Toxicology, Department of Medicine, Imperial College London, London W12 0NN, UK. Lightfoot T T Department of Health Sciences, University of York, York YO10 5DD, UK. Boobis A R AR Experimental Medicine and Toxicology, Department of Medicine, Imperial College London, London W12 0NN, UK. Gooderham N J NJ Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK. ENG JOURNAL ARTICLE 2014 10 21

Br J Cancer 0370635 0007-0920 2014 9 4 2014 9 16 2014 10 22 6 0 2014 10 22 6 0 2014 10 22 6 0 aheadofprint bjc2014540 10.1038/bjc.2014.540 25333344 25328136 2014 10 20 2014 10 21

1476-5594 2014 Oct 20 Oncogene DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. 10.1038/onc.2014.334 Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.Oncogene advance online publication, 20 October 2014; doi:10.1038/onc.2014.334. Lopez-Bertoni H H 1] Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Lal B B 1] Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Li A A Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA. Caplan M M Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA. Guerrero-Cázares H H Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA. Eberhart C G CG Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Quiñones-Hinojosa A A 1] Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA [2] Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA [3] Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Glas M M 1] Institute of Reconstructive Neurobiology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany [2] Department of Neurology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany [3] Clinical Cooperation Unit Neurooncology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany. Scheffler B B Institute of Reconstructive Neurobiology, MediClin Robert Janker Klinik and University of Bonn Medical Center, Bonn, Germany. Laterra J J 1] Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA [3] Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA [4] Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA. Li Y Y 1] Hugo W Moser Research Institute at Kennedy Krieger, Baltimore, MD, USA [2] Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA. ENG JOURNAL ARTICLE 2014 10 20

Oncogene 8711562 0950-9232 2014 4 14 2014 9 8 2014 9 10 2014 10 21 6 0 2014 10 21 6 0 2014 10 21 6 0 aheadofprint onc2014334 10.1038/onc.2014.334 25328136 25319395 2014 10 16 2014 10 17

1538-8514 2014 Oct 15 Mol. Cancer Ther. Involvement of microRNA-24 and DNA Methylation in Resistance of Nasopharyngeal Carcinoma to Ionizing Radiation. molcanther.0317.2014 Nasopharyngeal carcinoma (NPC) is a malignant tumor originating in the epithelium. Radiotherapy is the standard therapy, but tumor resistance to this treatment reduces the 5-year patient survival rate dramatically. Studies are urgently needed to elucidate the mechanism of NPC radioresistance. Epigenetics - particularly microRNAs (miRNAs) and DNA methylation - plays an important role in carcinogenesis and oncotherapy. We used qRT-PCR analysis and identified a miRNA signature from differentially expressed miRNAs. Our objectives were to identify the role of miR-24 in NPC tumorigenesis and radioresistance and to identify the mechanisms by which miR-24 is regulated. We found that miR-24 inhibited NPC cell growth, promoted cell apoptosis, and suppressed the growth of NPC xenografts. We showed that miR-24 was significantly downregulated in recurrent NPC tissues. When combined with irradiation, miR-24 acted as a radiosensitizer in NPC cells. One of the miR-24 precursors was embedded in a CpG island. Aberrant DNA methylation was involved in NPC response to radiotherapy, which linked inactivation of miR-24 through hypermethylation of its precursor promoter with NPC radioresistance. Treating NPC cells with the DNA-hypomethylating agent 5-aza-2'-deoxycytidine compensated for the reduced miR-24 expression. Together, our findings showed that miR-24 was negatively regulated by hypermethylation of its precursor promoter in NPC radioresistance. Our findings defined a central role for miR-24 as a tumor-suppressive miRNA in NPC and suggested its use in novel strategies for treatment of this cancer. Copyright © 2014, American Association for Cancer Research. Wang Sumei S Department of Systems Biology, The University of Texas MD Anderson Cancer Center. Zhang Rong R Department of Pathophysiology, Sun Yat-Sen University. Claret Francois X FX Systems Biology, The University of Texas MD Anderson Center Center fxclaret@mdanderson.org. Yang Huiling H Pathophysiology, Zhongshan School of Medicine, Sun Yat-Sen University. ENG JOURNAL ARTICLE 2014 10 15

Mol Cancer Ther 101132535 1535-7163 2014 10 17 6 0 2014 10 17 6 0 2014 10 17 6 0 aheadofprint 1535-7163.MCT-14-0317 10.1158/1535-7163.MCT-14-0317 25319395 25217977 2014 9 14

1432-1955 2014 Sep 14 Parasitol. Res. Induction of cancer-related microRNA expression profiling using excretory-secretory products of Clonorchis sinensis. Clonorchis sinensis is a carcinogenic human liver fluke by which chronic infection is strongly associated with the development of cholangiocarcinoma. Although this cholangiocarcinoma is caused by both physical and chemical irritation from direct contact with adult worms and their excretory-secretory products (ESPs), the precise molecular events of the host-pathogen interactions remain to be elucidated. To better understand the effect of C. sinensis infection on cholangiocarcinogenesis, we profiled the kinetics of changes in cancer-related microRNAs (miRNAs) in human cholangiocarcinoma cells (HuCCT1) treated with C. sinensis ESPs for different periods. Using miRNA microarray chips containing 135 cancer-related miRNAs, we identified 16 miRNAs showing differentially altered expression following ESP exposure. Of these miRNAs, 13 were upregulated and 3 were downregulated in a time-dependent manner compared with untreated controls. Functional clustering of these dysregulated miRNAs revealed involvement in cell proliferation, inflammation, oncogene activation/suppression, migration/invasion/metastasis, and DNA methylation. In particular, decreased expression of let-7i, a tumor suppressor miRNA, was found to be associated with the ESP-induced upregulation of TLR4 mRNA and protein, which contribute to host immune responses against liver fluke infection. Further real-time quantitative PCR analysis using ESP-treated normal cholangiocytes (H69) revealed that the expressions of nine miRNAs (miR-16-2, miR-93, miR-95, miR-153, miR-195, miR-199-3P, let7a, let7i, and miR-124a) were similarly regulated, indicating that the cell proliferation and inhibition of tumor suppression mediated by these miRNAs is common to both cancerous and non-cancerous cells. These findings constitute further our understanding of the multiple cholangiocarcinogenic pathways triggered by liver fluke infection. Pak Jhang Ho JH Asan Institute for Life Sciences, University of Ulsan College of Medicine Asan Medical Center, 388-1 Punganp-2 dong, Songpa-gu, Seoul, 138-736, Republic of Korea, jhpak@amc.seoul.kr. Kim In Ki IK Kim Seon Min SM Maeng Sejung S Song Kyoung Ju KJ Na Byoung-Kuk BK Kim Tong-Soo TS ENG JOURNAL ARTICLE 2014 9 14

Parasitol Res 8703571 0932-0113 2014 8 20 2014 8 29 2014 9 14 2014 9 15 6 0 2014 9 15 6 0 2014 9 15 6 0 aheadofprint 10.1007/s00436-014-4127-y 25217977 25205159 2014 9 24 2014 9 24

1879-016X 2014 Sep 7 Pharmacol. Ther. Epigenetic therapy as a novel approach in hepatocellular carcinoma. S0163-7258(14)00167-3 10.1016/j.pharmthera.2014.09.005 Hepatocellular carcinoma (HCC) is the most common type of liver malignancy and one with high fatality. Its 5-year survival rate remains low and thus, there is a need for improvement of current treatment strategies as well as development of novel targeted methodologies in order to optimize existing therapeutic protocols. To this end, only recently, it was discovered that its pathophysiology also involves epigenetic alterations in DNA methylation, histone modifications and/or non-coding microRNA patterns. Unlike genetic events, epigenetic alterations are reversible and thus potentially considered to be an alternative option in cancer treatment protocols. In this review, we describe the general characteristics and resulted major alterations of the epigenetic machinery as well as current state of progress of epigenetic therapy (via different single or combinatorial experimental approaches) in HCC. Copyright © 2014 Elsevier Inc. All rights reserved. Anestopoulos Ioannis I Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece. Voulgaridou Georgia Persephoni GP Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece. Georgakilas Alexandros G AG School of Applied Mathematical & Physical Sciences, National Technical University of Athens, Athens, Greece. Franco Rodrigo R Redox Biology Center, School of Veterinary Medicine & Biomedical Sciences, Redox Biology Center, University of Nebraska-Lincoln, USA. Pappa Aglaia A Department of Molecular Biology & Genetics, Democritus University of Thrace, Alexandroupolis, Greece. Panayiotidis Mihalis I MI School of Life Sciences, Heriot Watt University, Edinburgh, UK. Electronic address: M.Panagiotidis@hw.ac.uk. ENG REVIEW 2014 9 7

Pharmacol Ther 7905840 0163-7258 DNMT inhibitors Epigenetic modifications Epigenetic therapy HDAC inhibitors Hepatocellular carcinoma Natural products 2014 7 10 2014 9 2 2014 9 11 6 0 2014 9 11 6 0 2014 9 11 6 0 aheadofprint 25205159 S0163-7258(14)00167-3 10.1016/j.pharmthera.2014.09.005 25188512 2014 09 05

2041-4889 5 2014 Cell Death Dis The DNA methylation-regulated miR-193a-3p dictates the multi-chemoresistance of bladder cancer via repression of SRSF2/PLAU/HIC2 expression. e1402 10.1038/cddis.2014.367 Chemoresistance hinders the curative cancer chemotherapy. To define the role of the DNA methylation-regulated microRNA (miR) genes in the chemoresistance of bladder cancer, we performed both DNA methylomic and miRomic analyses of a multi-chemosensitive (5637) versus a multi-chemoresistant (H-bc) cell line and found that miR-193a-3p is hypermethylated/silenced in 5637 and hypomethylated/expressed in H-bc cells. A forced reversal of its level turned around the chemoresistance in the cultured cells and the tumor xenografts in nude mice. Three of its targets: SRSF2, PLAU and HIC2, work in concert to relay the miR-193a-3p's impact on the bladder cancer chemoresistance by modulating the activities of the following five signaling pathways: DNA damage, Notch, NF-κB, Myc/Max, and Oxidative Stress. In addition to the mechanistic insights in how the newly identified miR-193a-3p/SRSF2,PLAU,HIC2/five signaling pathway axis regulates the chemoresistance of bladder cancer cells, our study provides a new set of diagnostic targets for the guided personalized chemotherapy of bladder cancer. Lv L L Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China. Deng H H Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China. Li Y Y Department of Biology, School of Life Science, Anhui Medical University, Hefei, Anhui 230031, China. Zhang C C Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Liu X X Department of Bioinformatics, MHBI (Shanghai) Biotech Inc., GuiPing Road 333, Building 4/104, Shanghai Juke Biotech Park, Shanghai, China. Liu Q Q School of Life Science and Technology, State Key Laboratory of Urban Water Resource and Environment, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China. Zhang D D Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Wang L L Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China. Pu Y Y Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China. Zhang H H Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China. He Y Y Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China. Wang Y Y Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Yu Y Y Department of Urology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Yu T T Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China. Zhu J J 1] Cancer Epigenetics Program, Anhui Cancer Hospital, Hefei, Anhui 230031, China [2] Cancer Epigenetics Program, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, Shanghai 200032, China. eng Journal Article Research Support, Non-U.S. Gov't 2014 09 04

England Cell Death Dis 101524092 IM 2014 4 7 2014 6 30 2014 7 24 2014 9 5 6 0 2014 9 5 6 0 2014 9 5 6 0 epublish cddis2014367 10.1038/cddis.2014.367 25188512 25165988 2014 08 29

1478-6362 16 3 2014 Arthritis Res. Ther. The epigenome of synovial fibroblasts: an underestimated therapeutic target in rheumatoid arthritis. 117 Perturbed epigenetic landscape and deregulated microRNA networks are central to the permanent activation and aggressiveness of synovial fibroblasts in rheumatoid arthritis. Current anti-cytokine therapies, although effectively halting synovitis, cannot reverse the stably activated destructive phenotype of rheumatoid arthritis synovial fibroblasts,offering rather limited protection against ongoing joint destruction in rheumatoid arthritis. Targeting the deregulated epigenome of rheumatoid arthritis synovial fibroblasts is key to developing joint-protective strategies in rheumatoid arthritis. To date, different pathogenic mechanisms have been identified that can profoundly impact the epigenetic derangements in rheumatoid arthritis synovial fibroblasts, including increased consumption of S-adenosylmethionine,a principal methyl donor in DNA methylation reactions, together with deregulation of crucial DNA- and histonemodifying enzymes. Re-establishing globally disturbed DNA methylation patterns in rheumatoid arthritis synovial fibroblasts by supplementing S-adenosylmethionine while preventing its leakage into polyamine cycles may bea promising therapeutic strategy in rheumatoid arthritis and the first epigenetic treatment to target rheumatoid arthritis synovial fibroblasts at the scene of the crime. Given the dynamic nature and reversibility of epigenetic modifications, their involvement in human diseases and recent perspectives on epigenetic therapies in cancer, epigenetic targeting of rheumatoid arthritis synovial fibroblasts should be within future reach. Frank-Bertoncelj Mojca M Gay Steffen S eng Journal Article Research Support, Non-U.S. Gov't

England Arthritis Res Ther 101154438 1478-6354 IM PMC4075141 [Available on 12/26/14] 2014 6 26 2014 8 29 6 0 2014 8 29 6 0 2014 8 29 6 0 2014 12 26 0 0 ppublish ar4596 10.1186/ar4596 25165988 PMC4075141 25128828 2014 9 1

1090-2104 2014 Aug 13 Biochem. Biophys. Res. Commun. DNA methylation and microRNA biomarkers for noninvasive detection of gastric and colorectal cancer. S0006-291X(14)01406-5 10.1016/j.bbrc.2014.08.001 Cancer initiation and progression is controlled by both genetic and epigenetic events. Epigenetics refers to the study of mechanisms that alter gene expression without permanently altering the DNA sequence. Epigenetic alterations are reversible and heritable, and include changes in histone modifications, DNA methylation, and non-coding RNA-mediated gene silencing. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression. Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients. At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis. Following identification of cell-free nucleic acids in systematic circulation, increasing evidence has demonstrated the potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. In this article, we summarize the current state of knowledge on epigenetic biomarkers - primarily DNA methylation and non-coding RNAs - as potential substrates for cancer detection in gastric and colorectal cancer, the two most frequent cancers within the gastrointestinal tract. We also discuss the obstacles that have limited the routine use of epigenetic biomarkers in the clinical settings and provide our perspective on approaches that might help overcome these hurdles, so that these biomarkers can be readily developed for clinical management of cancer patients. Copyright © 2014 Elsevier Inc. All rights reserved. Toiyama Yuji Y Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan. Okugawa Yoshinaga Y Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA; Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie 514-8507, Japan. Goel Ajay A Gastrointestinal Cancer Research Laboratory, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246, USA. Electronic address: ajay.goel@baylorhealth.edu. ENG R01 CA072851 CA NCI NIH HHS United States REVIEW 2014 8 13

Biochem Biophys Res Commun 0372516 0006-291X Biomarker Colorectal cancer Diagnosis Gastric cancer Methylation MicroRNA 2014 6 21 2014 7 22 2014 8 1 2014 8 17 6 0 2014 8 17 6 0 2014 8 17 6 0 aheadofprint 25128828 S0006-291X(14)01406-5 10.1016/j.bbrc.2014.08.001 25053532 2014 7 23

1699-5848 2014 Jul 23 Histol. Histopathol. Fibroblast growth factor receptors: multifactorial-contributors to tumor initiation and progression. Fibroblast growth factor receptors (FGFRs), encoded by four genes (FGFR1, FGFR2, FGFR3, and FGFR4) are tightly associated with many biological processes such as organ development, cell proliferation and migration. Studies over the past decades have validated the pivotal roles FGFRs play in tumorigenesis due to the regulation of diverse tumorigenesis-related processes, including cell survival, proliferation, inflammation, metastasis and angiogenesis. Interestingly, FGFR mutations in somatic cells leading to tumorigenesis and those in germ cells leading to developmental disorders are identical, suggesting that FGFR mutations result in different diseases due to their spatio-temporal expression. Thus, discoveries in developmental biology may also be applicable to cancer. FGFRs regulate the expression and/or the activity of a myriad of molecules (e.g. matrix metalloproteinases (MMPs) and Snail) that are tightly linked to tumorigenesis by four main signaling pathways (RAS-MAPK, PI3K-AKT, PLCγ-PIP2, and STAT), as well as other minor branches. Epigenetic and genetic alteration of FGFR genes, including DNA methylation, histone remodeling, microRNA regulation, single nucleotide polymorphisms (SNPs), gene missense mutations, amplification, and fusion of FGFRs with other genes, which result in gain or loss of FGFR function, have been identified in many types of cancer. In this review, we focus in particular on recent advances in the relationship between FGFR disorders and tumorigenesis. Feng Shachuan S School of life science, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China. Zhou Li L School of life science, and The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China. Nice Edouard Collins EC Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. ed.nice@monash.edu. Huang Canhua C The State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, P.R. China. hcanhua@hotmail.com. ENG REVIEW 2014 7 23

Histol Histopathol 8609357 0213-3911 2014 7 24 6 0 2014 7 24 6 0 2014 7 24 6 0 aheadofprint HH-11-525 25053532 25032259 2014 07 16

1465-542X 16 2 2014 Breast Cancer Res. Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. 208 The idea that susceptibility to breast cancer is determined not only through inherited germline mutations but also by epigenetic changes induced by alterations in hormonal environment during fetal development is gaining increasing support. Using findings obtained in human and animal studies, this review addresses the mechanisms that may explain why daughters of mothers who took synthetic estrogen diethylstilbestrol (DES) during pregnancy have two times higher breast cancer risk than women who were not exposed to it. The mechanisms likely involve epigenetic alterations, such as increased DNA methylation and modifications in histones and microRNA expression.Further, these alterations may target genes that regulate stem cells and prevent differentiation of their daughter cells. Recent findings in a preclinical model suggest that not only are women exposed to DES in utero at an increased risk of developing breast cancer, but this risk may extend to their daughters and granddaughters as well. It is critical, therefore, to determine if the increased risk is driven by epigenetic alterations in genes that increase susceptibility to breast cancer and if these alterations are reversible. Hilakivi-Clarke Leena L eng P30 CA051668 CA NCI NIH HHS United States R01 CA164384 CA NCI NIH HHS United States U54 CA100970 CA NCI NIH HHS United States U54CA149147 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural

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1471-2407 14 2014 BMC Cancer Epigenetic silencing of genes and microRNAs within the imprinted Dlk1-Dio3 region at human chromosome 14.32 in giant cell tumor of bone. 495 10.1186/1471-2407-14-495 Growing evidence exists that the neoplastic stromal cell population (GCTSC) within giant cell tumors (GCT) originates from mesenchymal stem cells (MSC). In a previous study we identified a microRNA signature that differentiates between these cell types. Five differentially expressed microRNAs are located within the Dlk1-Dio3 region on chromosome 14. Aberrant regulation within this region is known to influence cell growth, differentiation and the development of cancer. The aim of this study was to elucidate the involvement of deregulations within the Dlk1-Dio3 region in GCT pathogenesis. Quantitative gene and microRNA expression analyses were performed on GCTSCs and MSCs with or without treatment with epigenetic modifiers. Methylation analysis of differentially methylated regions was performed by bisulfite sequencing. In addition to microRNA silencing we detected a significant downregulation of Dlk1, Meg3 and Meg8 in GCTSCs compared to MSCs. DNA methylation analyses of the Meg3-DMR and IG-DMR revealed a frequent hypermethylation within the IG-DMR in GCTs. Epigenetic modification could restore expression of some but not all analyzed genes and microRNAs suggesting further regulatory mechanisms. Epigenetic silencing of genes and microRNAs within the Dlk1-Dio3 region is a common event in GCTSCs, in part mediated by hypermethylation within the IG-DMR. The identified genes, micro RNAs and microRNA target genes might be valuable targets for the development of improved strategies for GCT diagnosis and therapy. Lehner Burkhard B Kunz Pierre P Saehr Heiner H Fellenberg Joerg J Research Centre for Experimental Orthopedics, Department of Orthopedics, Trauma Surgery and Paraplegia, Orthopedic University Hospital Heidelberg, Schlierbacher Landstr 200a, Heidelberg 69118, Germany. Joerg.Fellenberg@med.uni-heidelberg.de. eng Journal Article Research Support, Non-U.S. Gov't 2014 07 09

England BMC Cancer 100967800 1471-2407 IM J Mol Endocrinol. 2012 Jun;48(3):R45-53 22393162 Cancer Lett. 2012 Aug 28;321(2):162-8 22326282 Mol Cancer. 2012;11:44 22747855 PLoS One. 2012;7(11):e49462 23145177 Cell Mol Life Sci. 2013 Mar;70(5):795-814 22825660 Genes Cells. 2000 Mar;5(3):211-20 10759892 J Cancer Res Clin Oncol. 2001 Aug;127(8):467-74 11501745 Cancer Genet Cytogenet. 2002 Jun;135(2):177-81 12127403 Pathobiology. 2002-2003;70(6):333-42 12865629 Hum Pathol. 2003 Oct;34(10):983-93 14608531 Genome Res. 2004 Sep;14(9):1741-8 15310658 Chir Organi Mov. 1990;75(1 Suppl):206 2249534 Clin Orthop Relat Res. 1997 Feb;(335):253-61 9020226 J Orthop Res. 1998 Jan;16(1):1-7 9565066 Oncogene. 1998 Dec 10;17(23):3029-33 9881705 Cancer Genet Cytogenet. 1999 Jun;111(2):161-5 10347556 Br J Cancer. 2005 Apr 25;92(8):1574-80 15798773 Bioinformatics. 2005 Nov 1;21(21):4067-8 16141249 Hum Mol Genet. 2006 Mar 15;15(6):821-30 16439445 Mol Cancer. 2006;5:29 16854228 Nat Genet. 2008 Feb;40(2):237-42 18176563 Proc Natl Acad Sci U S A. 2008 May 13;105(19):7004-9 18458333 Trends Genet. 2008 Jun;24(6):306-16 18471925 Ann Diagn Pathol. 2008 Aug;12(4):239-48 18620989 Clin Lymphoma Myeloma. 2008 Jun;8(3):171-5 18650181 J Pathol. 2010 Jan;220(1):71-86 19768731 Lancet Oncol. 2010 Feb;11(2):136-46 20022810 Endocrinology. 2010 Mar;151(3):939-47 20032057 Nature. 2010 May 13;465(7295):175-81 20418860 J Biol Chem. 2010 Jun 18;285(25):19483-90 20382743 PLoS Genet. 2010 Jun;6(6):e1000992 20585555 Int J Cancer. 2010 Oct 15;127(8):1804-12 20104524 Clin Chem. 2010 Dec;56(12):1871-9 20943850 J Biol Chem. 2011 Sep 2;286(35):30706-13 21737452 Am J Pathol. 2011 Oct;179(4):2120-30 21871428 PMC4101709 2014 3 18 2014 7 4 2014 7 9 2014 7 10 6 0 2014 7 10 6 0 2014 7 10 6 0 epublish 1471-2407-14-495 10.1186/1471-2407-14-495 25005035 PMC4101709 25003254 2014 07 09

1949-2553 5 11 2014 Jun 15 Oncotarget nc886, a non-coding RNA of anti-proliferative role, is suppressed by CpG DNA methylation in human gastric cancer. 3944-55 nc886 is a 101 nucleotide long non-coding RNA that has been designated as a precursor microRNA or a vault RNA based upon it sequence. nc886 has also been suggested to be a tumor suppressor, mainly inferred by its expression pattern as well as its genomic location at human chromosome 5q31, a locus for a tumor suppressor gene(s). However, legitimate data based on nc886's correct identity for its functional cellular roles as a tumor suppressor have not been provided yet. Here we have investigated nc886 in gastric cancer where its expression is suppressed due to CpG DNA hypermethylation at its promoter region in a cohort of paired tumor/normal tissues from 88 gastric cancer patients. CpG hypermethylation of nc886 and thus its diminished expression is significantly associated with poor survival in these cancer patients. nc886 inhibits cell proliferation when ectopically expressed in gastric cancer cells. nc886's tumor suppressive role is corroborated by the induction of well-known oncogenes such as FOS, NF-κB, and MYC upon its knockdown. All these activities of nc886 are undoubtedly independent of mature microRNA or vault RNA. Our data indicate that nc886 is a putative tumor suppressor and could potentially be used as a diagnostic marker in gastric cancer. Lee Kwang-Soo KS Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX77555-1072, USA; Department of Life Science and Center for Aging and Health Care, Hallym University, Chuncheon 200-702, Korea. Park Jong-Lyul JL Lee Kwanbok K Richardson Lauren E LE Johnson Betty H BH Lee Hyun-Sung HS Lee Ju-Seog JS Kim Sang-Bae SB Kwon Oh-Hyung OH Song Kyu Sang KS Kim Yong Sung YS Ashktorab Hassan H Smoot Duane T DT Jeon Sung Ho SH Department of Life Science and Center for Aging and Health Care, Hallym University, Chuncheon 200-702, Korea. Kim Seon-Young SY Medical Genomics Research Center, KRIBB, Daejeon 305-806, Korea;Department of Functional Genomics, University of Science and Technology, Daejeon, 305-806, Korea. Lee Yong Sun YS Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX77555-1072, USA. eng G12MD007597 MD NIMHD NIH HHS United States G12RR003048 RR NCRR NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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1756-6614 7 2014 Thyroid Res New insights into the diagnosis of nodular goiter. 6 10.1186/1756-6614-7-6 PREOPERATIVE DIAGNOSTIC INVESTIGATIONS OF NODULAR GOITER ARE BASED ON TWO MAIN EXAMINATIONS: ultrasonography of the thyroid gland and ultrasound-guided fine-needle aspiration biopsy. So far, FNAB has been the best method for the differentiation of nodules, but in some cases it fails to produce a conclusive diagnosis. Some of the biopsies do not provide enough material to establish the diagnosis, in some other biopsies cytological picture is inconclusive. Determining the eligibility of thyroid focal lesions for surgery has been more and more often done with molecular methods. The most common genetic changes leading to the development of thyroid cancer include mutations, translocations and amplifications of genes, disturbances in gene methylation and dysregulation of microRNA. The mutations of Ras proto-oncogenes and BRAF gene as well as disturbances of DNA methylation in promoter regions of genes regulating cell cycle (e.g. hypermethylation of RASSF1A gene and TIMP-3 gene) play an important role in the process of neoplastic transformation of thyreocyte. The advances in molecular biology made it possible to investigate these genetic disturbances in DNA and/or RNA from peripheral blood, postoperative thyroid tissue material and cytology specimens obtained through fine-needle aspiration biopsy of focal lesions in the thyroid gland. As it became possible to analyze the mutations and methylation of genes from cell material obtained through fine-needle aspiration biopsy, it would be beneficial to introduce the techniques of molecular biology in the pre-operative diagnosis of nodular goiter as a valuable method, complementary to ultrasonography and FNAB. The knowledge obtained from molecular studies might help to determine the frequency of follow-up investigations in patients with nodular goiter and to select patients potentially at risk of developing thyroid cancer, which would facilitate their qualification for earlier strumectomy. Syrenicz Anhelli A Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Szczecin, Poland. Koziołek Monika M Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Szczecin, Poland. Ciechanowicz Andrzej A Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University, Szczecin, Poland. Sieradzka Anna A Department of Endocrinology, Metabolic Diseases and Internal Diseases, Pomeranian Medical University in Szczecin, Szczecin, Poland. Bińczak-Kuleta Agnieszka A Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University, Szczecin, Poland. Parczewski Miłosz M Department of Infectious Diseases and Hepatology, Pomeranian Medical University, Szczecin, Poland. eng Journal Article Review 2014 06 17

England Thyroid Res 101469037 1756-6614 PMC4076755 Genetic testing Nodular goiter Thyroid cancer 2014 2014 4 11 2014 5 21 2014 6 17 2014 7 3 6 0 2014 7 6 6 0 2014 7 6 6 1 epublish 10.1186/1756-6614-7-6 1756-6614-7-6 24987460 PMC4076755 24976726 2014 06 30

2219-2840 20 24 2014 Jun 28 World J. Gastroenterol. DNA methylation, microRNAs, and their crosstalk as potential biomarkers in hepatocellular carcinoma. 7894-913 10.3748/wjg.v20.i24.7894 Epigenetic alterations have been identified as a major characteristic in human cancers. Advances in the field of epigenetics have contributed significantly in refining our knowledge of molecular mechanisms underlying malignant transformation. DNA methylation and microRNA expression are epigenetic mechanisms that are widely altered in human cancers including hepatocellular carcinoma (HCC), the third leading cause of cancer related mortality worldwide. Both DNA methylation and microRNA expression patterns are regulated in developmental stage specific-, cell type specific- and tissue-specific manner. The aberrations are inferred in the maintenance of cancer stem cells and in clonal cell evolution during carcinogenesis. The availability of genome-wide technologies for DNA methylation and microRNA profiling has revolutionized the field of epigenetics and led to the discovery of a number of epigenetically silenced microRNAs in cancerous cells and primary tissues. Dysregulation of these microRNAs affects several key signalling pathways in hepatocarcinogenesis suggesting that modulation of DNA methylation and/or microRNA expression can serve as new therapeutic targets for HCC. Accumulative evidence shows that aberrant DNA methylation of certain microRNA genes is an event specifically found in HCC which correlates with unfavorable outcomes. Therefore, it can potentially serve as a biomarker for detection as well as for prognosis, monitoring and predicting therapeutic responses in HCC. Anwar Sumadi Lukman SL Sumadi Lukman Anwar, Department of Surgery, Faculty of Medicine Universitas Gadjah Mada, Yogyakarta 55281, Indonesia. Lehmann Ulrich U Sumadi Lukman Anwar, Department of Surgery, Faculty of Medicine Universitas Gadjah Mada, Yogyakarta 55281, Indonesia. eng Journal Article Research Support, Non-U.S. Gov't

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2219-2840 20 24 2014 Jun 28 World J. Gastroenterol. Epigenetics and pancreatic cancer: pathophysiology and novel treatment aspects. 7830-48 10.3748/wjg.v20.i24.7830 An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16(ink4a), are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients. Neureiter Daniel D Daniel Neureiter, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Jäger Tarkan T Daniel Neureiter, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Ocker Matthias M Daniel Neureiter, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. Kiesslich Tobias T Daniel Neureiter, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria. eng Journal Article

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2013 Feb 28;329(2):125-36 23196059 Adv Exp Med Biol. 2013;774:1-20 23377965 Br J Cancer. 2013 Feb 5;108(2):361-9 23329235 World J Gastroenterol. 2013 Feb 14;19(6):813-28 23430136 J Cell Physiol. 2013 Jun;228(6):1255-63 23139153 PMC4069312 DNA methylation Epigenetics Epithelial-mesenchymal transition Histone modification Pancreatic cancer Targeted therapy microRNA 2013 11 28 2014 2 7 2014 3 12 2014 7 1 6 0 2014 7 1 6 0 2014 7 1 6 0 ppublish 10.3748/wjg.v20.i24.7830 24976721 PMC4069312 24952901 2014 07 09 2014 10 28

1546-1696 32 7 2014 Jul Nat. Biotechnol. Assessing the clinical utility of cancer genomic and proteomic data across tumor types. 644-52 10.1038/nbt.2940 Molecular profiling of tumors promises to advance the clinical management of cancer, but the benefits of integrating molecular data with traditional clinical variables have not been systematically studied. Here we retrospectively predict patient survival using diverse molecular data (somatic copy-number alteration, DNA methylation and mRNA, microRNA and protein expression) from 953 samples of four cancer types from The Cancer Genome Atlas project. We find that incorporating molecular data with clinical variables yields statistically significantly improved predictions (FDR < 0.05) for three cancers but those quantitative gains were limited (2.2-23.9%). Additional analyses revealed little predictive power across tumor types except for one case. In clinically relevant genes, we identified 10,281 somatic alterations across 12 cancer types in 2,928 of 3,277 patients (89.4%), many of which would not be revealed in single-tumor analyses. Our study provides a starting point and resources, including an open-access model evaluation platform, for building reliable prognostic and therapeutic strategies that incorporate molecular data. Yuan Yuan Y 0000000347067897 1] Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [3]. Van Allen Eliezer M EM 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3]. Omberg Larsson L 1] Sage Bionetworks, Seattle, Washington, USA. [2]. Wagle Nikhil N 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Amin-Mansour Ali A Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Sokolov Artem A Department of Biomolecular Engineering, University of California, Santa Cruz, California, USA. Byers Lauren A LA Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Xu Yanxun Y Division of Statistics and Scientific Computing, The University of Texas at Austin, Austin, Texas, USA. Hess Kenneth R KR Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Diao Lixia L Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Han Leng L Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Huang Xuelin X Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Lawrence Michael S MS Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. Weinstein John N JN 1] Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [2] Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Stuart Josh M JM Department of Biomolecular Engineering, University of California, Santa Cruz, California, USA. Mills Gordon B GB Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Garraway Levi A LA 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [3] Harvard Medical School, Boston, Massachusetts, USA. [4]. Margolin Adam A AA 1] Sage Bionetworks, Seattle, Washington, USA. [2] [3]. Getz Gad G 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Massachusetts General Hospital, Cancer Center and Department of Pathology, Boston, Massachusetts, USA. [4]. Liang Han H 000000017633286X 1] Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas, USA. [2] Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. [3]. eng CA016672 CA NCI NIH HHS United States CA143883 CA NCI NIH HHS United States CA175486 CA NCI NIH HHS United States P50 CA098258 CA NCI NIH HHS United States R01 CA175486 CA NCI NIH HHS United States U24 CA143883 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2014 06 22

United States Nat Biotechnol 9604648 1087-0156 0 DNA, Neoplasm 0 Genetic Markers 0 Proteome 0 Tumor Markers, Biological IM DNA, Neoplasm genetics Databases, Genetic Genetic Markers genetics Genetic Predisposition to Disease epidemiology genetics Humans Neoplasms classification genetics mortality Prevalence Proteome genetics Risk Assessment Survival Analysis Tumor Markers, Biological genetics NIHMS600159 [Available on 01/01/15] PMC4102885 [Available on 01/01/15] 2013 5 31 2014 5 28 2014 6 22 2014 6 23 6 0 2014 6 24 6 0 2014 10 29 6 0 2015 1 1 0 0 ppublish nbt.2940 10.1038/nbt.2940 24952901 PMC4102885 NIHMS600159 24932239 2014 6 16

1792-1074 7 6 2014 Jun Oncol Lett Modulation of microRNA expression in human lung cancer cells by the G9a histone methyltransferase inhibitor BIX01294. 1819-1825 MicroRNAs (miRNAs) are small non-coding RNAs that regulate the expression of their target genes at the post-transcriptional level. In cancer cells, miRNAs, depending on the biological functions of their target genes, may have a tumor-promoting or -suppressing effect. Treatment of cancer cells with inhibitors of DNA methylation and/or histone deacetylation modulates the expression level of miRNAs, which provides evidence for epigenetic regulation of miRNA expression. The consequences of inhibition of histone methyltransferase on miRNA expression, however, have not been thoroughly investigated. The present study examined the expression pattern of miRNAs in the non-small cell lung cancer cell line, H1299 with or without treatment of BIX01294, a potent chemical inhibitor of G9a methyltransferase that catalyzes the mono-and di-methylation of the lysine 9 residue of histone H3. By coupling microarray analysis with quantitative real-time polymerase chain reaction analysis, two miRNAs were identified that showed consistent downregulation following BIX01294 treatment. The results indicate that histone H3 methylation regulates miRNA expression in lung cancer cells, which may provide additional insight for future chemical treatment of lung cancer. Pang Alan Lap-Yin AL Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4429, USA. Title Alexandra C AC Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4429, USA. Rennert Owen M OM Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-4429, USA. ENG JOURNAL ARTICLE 2014 4 04

Oncol Lett 101531236 1792-1074 BIX01294 G9a methyltransferase H1299 lung cancer microRNA 2013 9 03 2014 3 14 2014 4 04 2014 6 17 6 0 2014 6 17 6 0 2014 6 17 6 0 ppublish 10.3892/ol.2014.2034 ol-07-06-1819 24932239 PMC4049738 24920927 2014 06 12 2014 06 12 2014 06 16

1178-6930 7 2014 Onco Targets Ther Clinical significance of promoter region hypermethylation of microRNA-148a in gastrointestinal cancers. 853-63 10.2147/OTT.S60888 MicroRNAs are associated with tumor genesis and progression in various carcinomas. MicroRNA-148a (miR-148a) was reported to have low expression in gastrointestinal cancers, and might be regulated by promoter region DNA methylation. Bisulfite-modified sequencing was used to determine the promoter region DNA methylation status of human gastrointestinal cancer cell lines. Expression levels of miR-148a in cell lines treated with 5-aza-2'-deoxycytidine were determined by quantitative real-time polymerase chain reaction. Total DNA was extracted from the tissues of 64 patients with gastric cancer and 51 patients with colorectal cancer. Methylation status was determined by methylation-specific polymerase chain reaction. All statistical analyses were performed with SPSS 17.0 software. The promoter regions of genes in human gastrointestinal cancer cell lines were all hypermethylated, except for HT-29, and the expression of miR-148a tended to be higher than in controls after treatment with 5-aza-2'-deoxycytidine. The methylation-specific polymerase chain reaction results showed that 56.25% of gastric cancer tissues and 19.61% of colorectal cancer tissues were hypermethylated. A strong correlation was found between the expression of miR-148a and the methylation status of promoter regions (P<0.001, chi-square test and Pearson's correlation). Furthermore, promoter region CpG site hypermethylation of miR-148a was correlated with increased tumor size (P=0.01) in gastric cancer after analyzing the correlation between methylation status and clinicopathologic characteristics. The promoter region CpG sites were hypermethylated in gastrointestinal cancers. Promoter region hypermethylation status was associated with the expression of miR-148a and tumor invasiveness in gastric cancer, and may prove to be a new biomarker and method for treating gastric cancer. Sun Jingxu J Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Song Yongxi Y Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Wang Zhenning Z Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Wang Guoli G Department of Biochemistry and Molecular Biology, China Medical University, Shenyang, People's Republic of China. Gao Peng P Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Chen Xiaowan X Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Gao Zhaohua Z Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. Xu Huimian H Department of Surgical Oncology and General Surgery, First Hospital of China Medical University, Shenyang, People's Republic of China. eng Journal Article 2014 05 28

New Zealand Onco Targets Ther 101514322 1178-6930 PMC4045258 CpG site clinicopathologic characteristics methylation microRNAs 2014 2014 5 28 2014 6 13 6 0 2014 6 13 6 0 2014 6 13 6 1 epublish 10.2147/OTT.S60888 ott-7-853 24920927 PMC4045258 24825593 2014 09 13 2014 11 07

1573-2568 59 10 2014 Oct Dig. Dis. Sci. DNA methylation of microRNA-124a is a potential risk marker of colitis-associated cancer in patients with ulcerative colitis. 2444-51 10.1007/s10620-014-3193-4 Colitis-associated cancer (CAC) is the serious complication of ulcerative colitis (UC), and molecular markers to evaluate the individual risk are required. MicroRNA-124a (miR - 124a) is known to have tumor-suppressive function and be methylation-silenced during exposure to chronic inflammation. We analyzed whether higher methylation levels of miR-124a genes correlated with the higher epidemiologic risk of CAC development in UC patients. Forty UC patients without CAC, four patients with CAC or dysplasia, eight sporadic colorectal cancer (S-CRC) patients, and 12 healthy volunteers (HV) were studied. Methylation status of miR-124a genes (miR-124a-1, -2, and -3) was analyzed by methylation-specific polymerase chain reaction (MSP), and methylation levels were quantified by real-time MSP. Expression of cyclin-dependent kinase 6 (CDK6), a target of miR-124a, was analyzed by immunohistochemistry. Three miR-124a genes were methylated in all neoplastic tissues (CAC, dysplasia, and S-CRC), and CDK6 was highly expressed in those tissues. Regarding disease extent, mean methylation levels of miR-124a-3 in HV, non-pancolitis, and pancolitis were 2.0, 5.3, and 12.3%, respectively, and were significantly higher in pancolitis than in HV (p < 0.01). Regarding disease duration, mean methylation levels in short-term and long-standing UC patients were 2.5 and 13.2%, respectively. Long-standing UC patients had significantly higher methylation levels than HV (p < 0.01). Moreover, UC patients with both pancolitis and long-standing had 7.4-fold higher methylation levels than those without these risk factors. MiR-124a genes are methylated during carcinogenesis in UC patients. The methylation level of miR-124a-3 is a promising marker for estimating individual risk for CAC. Ueda Yuko Y Department of Gastroenterology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan, i-yuko@umail.plala.or.jp. Ando Takayuki T Nanjo Sohachi S Ushijima Toshikazu T Sugiyama Toshiro T eng Journal Article 2014 05 10

United States Dig Dis Sci 7902782 0163-2116 0 Biological Markers 0 MIRN124 microRNA, human 0 MicroRNAs AIM IM Adult Aged Animals Biological Markers Cell Line, Tumor Colitis, Ulcerative complications metabolism Colonic Neoplasms etiology metabolism DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation physiology Humans Immunohistochemistry Male MicroRNAs genetics metabolism Middle Aged Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Risk Factors Young Adult 2014 1 15 2014 4 28 2014 5 10 2014 5 15 6 0 2014 5 16 6 0 2014 11 8 6 0 ppublish 10.1007/s10620-014-3193-4 24825593 24798303 2014 08 26 2014 10 30

1527-3350 60 3 2014 Sep Hepatology Modulation of miR-29 expression by α-fetoprotein is linked to the hepatocellular carcinoma epigenome. 872-83 10.1002/hep.27200 Globally, hepatocellular carcinoma (HCC) accounts for 70%-85% of primary liver cancers and ranks as the second leading cause of male cancer death. Serum alpha-fetoprotein (AFP), normally highly expressed in the liver only during fetal development, is reactivated in 60% of HCC tumors and associated with poor patient outcome. We hypothesize that AFP+ and AFP- tumors differ biologically. Multivariable analysis in 237 HCC cases demonstrates that AFP level predicts poor survival independent of tumor stage (P<0.043). Using microarray-based global microRNA (miRNA) profiling, we found that miRNA-29 (miR-29) family members were the most significantly (P<0.001) down-regulated miRNAs in AFP+ tumors. Consistent with miR-29's role in targeting DNA methyltransferase 3A (DNMT3A), a key enzyme regulating DNA methylation, we found a significant inverse correlation (P<0.001) between miR-29 and DNMT3A gene expression, suggesting that they might be functionally antagonistic. Moreover, global DNA methylation profiling reveals that AFP+ and AFP- HCC tumors have distinct global DNA methylation patterns and that increased DNA methylation is associated with AFP+ HCC. Experimentally, we found that AFP expression in AFP- HCC cells induces cell proliferation, migration, and invasion. Overexpression of AFP, or conditioned media from AFP+ cells, inhibits miR-29a expression and induces DNMT3A expression in AFP- HCC cells. AFP also inhibited transcription of the miR-29a/b-1 locus, and this effect is mediated through c-MYC binding to the transcript of miR-29a/b-1. Furthermore, AFP expression promotes tumor growth of AFP- HCC cells in nude mice. Tumor biology differs considerably between AFP+ HCC and AFP- HCC; AFP is a functional antagonist of miR-29, which may contribute to global epigenetic alterations and poor prognosis in HCC. © 2014 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA. Parpart Sonya S Laboratory of Human Carcinogenesis, National Cancer Institute, Bethesda, MD; Tumor Biology Department, Georgetown University, Washington, DC. Roessler Stephanie S Dong Fei F Rao Vinay V Takai Atsushi A Ji Junfang J Qin Lun-Xiu LX Ye Qing-Hai QH Jia Hu-Liang HL Tang Zhao-You ZY Wang Xin Wei XW eng Z01 BC 010313 BC NCI NIH HHS United States ZIA BC010313-14 BC NCI NIH HHS United States Journal Article Research Support, N.I.H., Intramural 2014 07 25

United States Hepatology 8302946 0270-9139 0 MIRN29 microRNA, human 0 MicroRNAs 0 alpha-Fetoproteins IM Adult Animals Carcinoma, Hepatocellular enzymology genetics mortality Cell Line, Tumor Cohort Studies DNA Methylation genetics Down-Regulation genetics Epigenomics Female Gene Expression Regulation, Neoplastic Humans Liver Neoplasms enzymology genetics mortality Liver Neoplasms, Experimental enzymology genetics mortality Male Mice Mice, Nude MicroRNAs antagonists & inhibitors biosynthesis genetics Middle Aged alpha-Fetoproteins biosynthesis genetics NIHMS593803 [Available on 09/01/15] PMC4146718 [Available on 09/01/15] 2013 10 24 2014 4 29 2014 7 25 2014 5 7 6 0 2014 5 7 6 0 2014 10 31 6 0 2015 9 1 0 0 ppublish 10.1002/hep.27200 24798303 PMC4146718 NIHMS593803 24785261 2014 08 23

1559-2308 9 7 2014 Jul Epigenetics Epigenetically regulated MIR941 and MIR1247 target gastric cancer cell growth and migration. 1018-30 10.4161/epi.29007 Altered expression of microRNA (miRNA) can significantly contribute to cancer development and recent studies have shown that a number of miRNAs may be regulated by DNA methylation. Through a candidate gene approach, we identified MIR941 and MIR1247 to be transcriptionally silenced by DNA hypermethylation in several gastric cancer cell lines. We confirmed that these miRNAs are also densely methylated in primary gastric cancers but not in normal gastric tissues. In addition, we demonstrated that ectopic expression of these two miRNAs in AGS gastric cancer cells resulted in suppression of growth and migration. Furthermore, we tested genes predicted to be the targets of MIR941 and MIR1247 and identified 7 and 6 genes, whose expressions were significantly downregulated by transfection of MIR941 and MIR1247 mimics, respectively, in gastric cancer cell lines. Some of these genes are known to promote proliferation and invasion, phenotypes we observed upon ectopic expression of the two miRNAs. Thus, we examined these candidates more closely and found that downregulation of mRNA corresponded to a decrease in protein levels (observed by western blot). Our study provides unequivocal evidence that MIR941 and MIR1247 are transcriptionally regulated by DNA methylation in gastric cancer and that they have tumor suppressor properties through their inhibition of key cancer promoting genes in this context. Kim Joong-Gook JG Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea. Kim Tae-Oh TO Department of Internal Medicine; Inje University Haeundae Paik Hospital; Busan, South Korea. Bae Jin-Han JH Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea. Shim Jae-Woong JW Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea. Kang Myoung Joo MJ Department of Internal Medicine; Inje University Haeundae Paik Hospital; Busan, South Korea. Yang Kwangmo K Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea. Ting Angela H AH Genomic Medicine Institute; Lerner Research Institute; Cleveland Clinic Foundation; Cleveland, OH USA. Yi Joo Mi JM Research Center; Dongnam Institute of Radiological & Medical Sciences (DIRAMS); Busan, South Korea. eng Journal Article Research Support, Non-U.S. Gov't 2014 05 28

United States Epigenetics 101265293 1559-2294 IM PMC4143404 [Available on 07/01/15] 5-aza-2'-deoxycytidine DNA methylation MIR1247 MIR941 epigenetics gastric cancer microRNA 2014 5 28 2014 5 3 6 0 2014 5 3 6 0 2014 5 3 6 0 2015 7 1 0 0 ppublish 24785261 29007 10.4161/epi.29007 PMC4143404 24782983 2014 04 30 2014 06 24 2014 06 24

2234-943X 4 2014 Front Oncol Molecular epigenetics in the management of ovarian cancer: are we investigating a rational clinical promise? 71 10.3389/fonc.2014.00071 Epigenetics is essentially a phenotypical change in gene expression without any alteration of the DNA sequence; the emergence of epigenetics in cancer research and mainstream oncology is fueling new hope. However, it is not yet known whether this knowledge will translate to improved clinical management of ovarian cancer. In this malignancy, women are still undergoing chemotherapy similar to what was approved in 1978, which to this day represents one of the biggest breakthroughs for treating ovarian cancer. Although liquid tumors are benefiting from epigenetically related therapies, solid tumors like ovarian cancer are not (yet?). Herein, we will review the science of molecular epigenetics, especially DNA methylation, histone modifications and microRNA, but also include transcription factors since they, too, are important in ovarian cancer. Pre-clinical and clinical research on the role of epigenetic modifications is also summarized. Unfortunately, ovarian cancer remains an idiopathic disease, for the most part, and there are many areas of patient management, which could benefit from improved technology. This review will also highlight the evidence suggesting that epigenetics may have pre-clinical utility in pharmacology and clinical applications for prognosis and diagnosis. Finally, drugs currently in clinical trials (i.e., histone deacetylase inhibitors) are discussed along with the promise for epigenetics in the exploitation of chemoresistance. Whether epigenetics will ultimately be the answer to better management in ovarian cancer is currently unknown; but we hope so in the future. Nguyen Ha T HT Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy , Athens, GA , USA. Tian Geng G Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy , Athens, GA , USA ; Department of Obstetrics and Gynecology, The Second Hospital of Jilin University , Changchun , China. Murph Mandi M MM Department of Pharmaceutical and Biomedical Sciences, University of Georgia College of Pharmacy , Athens, GA , USA. eng Journal Article Review 2014 04 08

Switzerland Front Oncol 101568867 2234-943X PMC3986558 DNA methylation epigenetics histone modifications microRNA ovarian cancer 2014 2014 1 23 2014 3 20 2014 4 08 2014 5 1 6 0 2014 5 2 6 0 2014 5 2 6 1 epublish 10.3389/fonc.2014.00071 24782983 PMC3986558 24769899 2014 4 28

1476-5594 0 2014 Apr 28 Oncogene miR-615-5p is epigenetically inactivated and functions as a tumor suppressor in pancreatic ductal adenocarcinoma. 10.1038/onc.2014.101 Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive cancer with a poor prognosis. Although microRNA (miRNA) transcripts have a crucial role in carcinogenesis and development, little information is known regarding the aberrant DNA methylation of miRNAs in PDAC. Using methylated DNA immunoprecipitation-chip analysis, we found that miR-615-5p was hypermethylated in its putative promoter region, which silenced its expression in PDAC cell lines. In addition, the overexpression of miR-615-5p in pancreatic cancer cells suppressed cell proliferation, migration and invasion. Insulin-like growth factor 2 (IGF2) is an imprinted gene, and its abnormal expression contributes to tumor growth. Here, we identified IGF2 as a target of miR-615-5p using a luciferase reporter assay. IGF2 upregulation in PDAC tissues was not correlated with a loss of imprinting but was inversely correlated with miR-615-5p downregulation. In addition, miR-615-5p suppressed pancreatic cancer cell proliferation, migration and invasion by directly targeting IGF2, and this effect could be reversed by co-transfection with IGF2. Furthermore, the stable overexpression of miR-615-5p inhibited tumor growth in vivo and was correlated with IGF2 expression. Using RNA sequencing, we further identified miR-615-5p as potentially targeting other genes, such as the proto-oncogene JUNB, and interfering with the insulin signaling pathway. Taken together, our results demonstrate that miR-615-5p was abnormally downregulated in PDAC cells due to promoter hypermethylation, which limited its inhibition of IGF2 and other target genes, thereby contributing to tumor growth, invasion and migration. These data demonstrate a novel and important role of miR-615-5p as a tumor suppressor in PDAC.Oncogene advance online publication, 28 April 2014; doi:10.1038/onc.2014.101. Gao W W Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Gu Y Y Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Li Z Z Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Cai H H Department of Hepato-Biliary Surgery, The First People's Hospital of Changzhou, Changzhou, China. Peng Q Q Department of General Surgery, The PLA 105 Hospital, Hefei, China. Tu M M Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Kondo Y Y Division of Epigenomics, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Japan. Shinjo K K Division of Epigenomics, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Japan. Zhu Y Y Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Zhang J J Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Sekido Y Y Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Japan. Han B B Department of Endocrinology, Nanjing Children's Hospital Affiliated with Nanjing Medical University, Nanjing, China. Qian Z Z Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. Miao Y Y Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. ENG JOURNAL ARTICLE 2014 4 28

Oncogene 8711562 0950-9232 2013 5 13 2014 3 2 2014 3 4 2014 4 29 6 0 2014 4 29 6 0 2014 4 29 6 0 aheadofprint onc2014101 10.1038/onc.2014.101 24769899 24764665 2014 04 25

2219-2840 20 15 2014 Apr 21 World J. Gastroenterol. Advances in epigenetic biomarker research in colorectal cancer. 4276-87 10.3748/wjg.v20.i15.4276 Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use. Wang Xi X Xi Wang, Ye-Ye Kuang, Xiao-Tong Hu, Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou 310016, Zhejiang Province, China. Kuang Ye-Ye YY Xi Wang, Ye-Ye Kuang, Xiao-Tong Hu, Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou 310016, Zhejiang Province, China. Hu Xiao-Tong XT Xi Wang, Ye-Ye Kuang, Xiao-Tong Hu, Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University and Key Laboratory of Biotherapy of Zhejiang Province, Hangzhou 310016, Zhejiang Province, China. eng Journal Article Research Support, Non-U.S. Gov't

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1791-2431 31 6 2014 Jun Oncol. Rep. Human papilloma virus, DNA methylation and microRNA expression in cervical cancer (Review). 2467-76 10.3892/or.2014.3142 Cancer is a complex disease caused by genetic and epigenetic abnormalities that affect gene expression. The progression from precursor lesions to invasive cervical cancer is influenced by persistent human papilloma virus (HPV) infection, which induces changes in the host genome and epigenome. Epigenetic alterations, such as aberrant miRNA expression and changes in DNA methylation status, favor the expression of oncogenes and the silencing of tumor-suppressor genes. Given that some miRNA genes can be regulated through epigenetic mechanisms, it has been proposed that alterations in the methylation status of miRNA promoters could be the driving mechanism behind their aberrant expression in cervical cancer. For these reasons, we assessed the relationship among HPV infection, cellular DNA methylation and miRNA expression. We conclude that alterations in the methylation status of protein-coding genes and various miRNA genes are influenced by HPV infection, the viral genotype, the physical state of the viral DNA, and viral oncogenic risk. Furthermore, HPV induces deregulation of miRNA expression, particularly at loci near fragile sites. This deregulation occurs through the E6 and E7 proteins, which target miRNA transcription factors such as p53. Jiménez-Wences Hilda H Clinical Research Laboratory, Academic Unit of Biological Chemical Sciences, Guerrero Autonomous University, Colonia Haciendita, Chilpancingo, Guerrero 39070, Mexico. Peralta-Zaragoza Oscar O Direction of Chronic Infections and Cancer, Research Center for Infectious Diseases, National Institute of Public Health, Cerrada los Pinos y Caminera, Colonia Santa María Ahuacatitlán, Cuernavaca, Morelos 62100, Mexico. Fernández-Tilapa Gloria G Clinical Research Laboratory, Academic Unit of Biological Chemical Sciences, Guerrero Autonomous University, Colonia Haciendita, Chilpancingo, Guerrero 39070, Mexico. eng Journal Article Research Support, Non-U.S. Gov't 2014 04 16

Greece Oncol Rep 9422756 1021-335X IM Dev Cell. 2010 Nov 16;19(5):698-711 21074720 Biochem Biophys Res Commun. 2010 Dec 17;403(3-4):357-62 21078297 J Int Med Res. 2010 Sep-Oct;38(5):1730-6 21309487 Asian Pac J Cancer Prev. 2010;11(6):1741-4 21338225 Virchows Arch. 2011 Mar;458(3):313-22 21225432 Cancer Biol Ther. 2011 Mar 1;11(5):490-6 21383543 Mol Med Rep. 2011 Jan-Feb;4(1):121-8 21461574 FEBS J. 2011 May;278(10):1598-609 21395977 PLoS One. 2011;6(5):e19503 21572997 Cancer Res. 2011 May 15;71(10):3552-62 21444677 Br J Cancer. 2011 May 24;104(11):1770-8 21610744 Epigenetics. 2011 Jun;6(6):740-51 21562367 Virol J. 2011;8:269 21635792 Exp Mol Med. 2011 Jun 30;43(6):358-66 21519184 PLoS One. 2011;6(7):e21646 21747943 Mol Med. 2011;17(7-8):726-35 21327300 Br J Haematol. 2011 Sep;154(5):569-78 21707582 Int J Cancer. 2011 Dec 1;129(11):2600-10 21960261 Neoplasia. 2011 Sep;13(9):841-53 21969817 Biochim Biophys Acta. 2011 Nov-Dec;1809(11-12):668-77 21616186 Cancer Sci. 2011 Dec;102(12):2126-31 21917081 Int J Mol Sci. 2013;14(7):14171-84 23880861 BMC Med Genet. 2013;14:74 23870168 Oncol Rep. 2013 Oct;30(4):1976-84 23900443 J Virol. 2004 Dec;78(23):12762-72 15542628 Cancer Res. 2005 May 1;65(9):3624-32 15867357 Cell Cycle. 2006 Oct;5(19):2220-2 17012846 Blood. 2006 Dec 1;108(12):3646-53 16882713 Oncogene. 2007 Mar 8;26(11):1650-5 16983344 Virology. 2007 Apr 25;361(1):185-93 17175003 Cell Cycle. 2007 Jun 15;6(12):1455-9 17581274 Cancer Res. 2007 Jul 1;67(13):6031-43 17616659 Br J Cancer. 2007 Nov 19;97(10):1457-64 17971771 Mol Cancer. 2007;6:60 17894887 Int J Cancer. 2008 Mar 1;122(5):963-8 18098137 Oncogene. 2008 Apr 17;27(18):2575-82 17998940 Clin Cancer Res. 2008 May 1;14(9):2535-42 18451214 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Cancer Res. 2008 Jul 1;68(13):5049-58 18593903 PLoS One. 2008;3(7):e2557 18596939 Cardiovasc Res. 2008 Sep 1;79(4):553-61 18539629 Cancer. 2008 Nov 15;113(10 Suppl):2981-94 18980282 Mamm Genome. 2008 Aug;19(7-8):517-25 18688563 PLoS One. 2009;4(3):e4941 19293934 Asian Pac J Cancer Prev. 2009 Jul-Sep;10(3):355-60 19640172 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 Mamm Genome. 2009 Sep-Oct;20(9-10):573-80 19697081 Cytokine Growth Factor Rev. 2009 Oct-Dec;20(5-6):517-21 19892582 Mol Cell. 2010 May 14;38(3):323-32 20471939 Cancer Res. 2010 Jul 15;70(14):5807-17 20570896 Int J Cancer. 2010 Sep 1;127(6):1363-72 20073067 PLoS One. 2010;5(7):e11780 20668671 PLoS One. 2010;5(7):e11794 20668688 Mol Cancer. 2010;9:167 20579385 P R Health Sci J. 2010 Sep;29(3):232-40 20799510 Oncol Rep. 2010 Dec;24(6):1599-604 21042757 Biochem Biophys Res Commun. 2013 Aug 16;438(1):48-53 23867826 Curr Pharm Des. 2014;20(11):1639-46 23888945 Cancer Res. 2009 Dec 1;69(23):9038-46 19887623 Cancer Res. 2010 Feb 15;70(4):1441-8 20124485 J Adolesc Health. 2010 Apr;46(4 Suppl):S20-6 20307840 PLoS One. 2011;6(11):e27722 22110741 Epigenomics. 2009 Oct;1(1):99-110 22122639 PLoS One. 2011;6(11):e27740 22140464 Epigenetics. 2011 Oct 1;6(10):1189-97 21931274 Epigenomics. 2009 Dec;1(2):239-59 20495664 Methods Mol Biol. 2012;863:155-76 22359292 Mol Cancer. 2012;11:5 22289355 Clin Cancer Res. 2012 Mar 15;18(6):1619-29 22282464 PLoS One. 2012;7(3):e33762 22438992 Oncogene. 2012 Mar 29;31(13):1609-22 21860412 Med Oncol. 2012 Jun;29(2):1242-8 21264530 PLoS One. 2012;7(7):e41012 22815898 Carcinogenesis. 2012 Jul;33(7):1286-93 22552403 Cell Cycle. 2012 Aug 1;11(15):2876-84 22801550 Med Oncol. 2012 Dec;29(4):2701-9 22167392 RNA Biol. 2012 Jun;9(6):881-90 22617881 Chin Med J (Engl). 2012 Dec;125(23):4270-6 23217399 J Infect Chemother. 2012 Dec;18(6):807-15 23117294 Chin J Cancer. 2013 Jan;32(1):42-8 22943599 Oncogene. 2013 Jan 3;32(1):127-34 22310291 Oncogene. 2013 Jan 3;32(1):106-16 22330141 PLoS One. 2013;8(1):e54398 23342147 Int J Cancer. 2013 May 1;132(9):2087-94 23065631 Epigenetics. 2013 Feb;8(2):220-8 23324622 Gene. 2013 Apr 15;518(2):351-9 23333942 Oncogene. 2013 Jun 6;32(23):2891-9 22869146 Virol J. 2013;10:175 23732000 Anticancer Res. 2013 Jun;33(6):2561-7 23749909 Int J Mol Med. 2013 Sep;32(3):557-67 23799609 PMC4055305 2014 1 14 2014 3 13 2014 4 16 2014 4 17 6 0 2014 4 17 6 0 2014 4 17 6 0 ppublish 10.3892/or.2014.3142 24737381 PMC4055305 24704024 2014 04 28 2014 07 02

1879-0038 543 1 2014 Jun 10 Gene Methylation-associated silencing of microRNA-34b in hepatocellular carcinoma cancer. 101-7 10.1016/j.gene.2014.03.059 S0378-1119(14)00397-7 MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human cancers including HCC. Previous studies have identified miR-34 family as an important component of the tumor suppressor network during carcinogenesis. In this study, we investigated the methylation status of miR-34 family in HCC tumor and adjacent non-tumor tissues using methylation-specific PCR (MSP). The methylation frequencies of miR-34a and miR-34b/c were 72.1% (31/43) and 79.1% (34/43) in HCC tissues, which were significantly higher than that in the adjacent non-tumor tissues (P < 0.05), respectively. The results were validated by bisulfite sequencing PCR (BSP). Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis showed that the expression of miR-34a and miR-34b was significantly down-regulated in HCC tissues compared with adjacent non-tumor tissues (P < 0.05). Moreover, the expression of miR-34b was inversely correlated to CpG island methylation in tumor tissues, but not for miR-34a. In summary, our results suggest that DNA methylation may be involved in the inactivation of miR-34b in HCC. Copyright © 2014 Elsevier B.V. All rights reserved. Xie Kaipeng K Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Liu Jibin J Tumor Institute, Nantong Tumor Hospital, Nantong 226361, Jiangsu Province, China. Electronic address: tians2008@163.com.cn. Chen Jiaping J Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Dong Jing J Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Ma Hongxia H Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Liu Yao Y Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China. Hu Zhibin Z Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China. Electronic address: zhibin_hu@njmu.edu.cn. eng Journal Article Research Support, Non-U.S. Gov't 2014 04 01

Netherlands Gene 7706761 0378-1119 0 MIRN34 microRNA, human 0 MicroRNAs IM Adult Aged Aged, 80 and over Carcinoma, Hepatocellular genetics CpG Islands DNA Methylation physiology Female Gene Expression Regulation, Neoplastic Gene Silencing Humans Liver Neoplasms genetics Male MicroRNAs genetics Middle Aged Hepatocellular carcinoma Methylation miR-34a miR-34b/c 2014 1 11 2014 3 28 2014 3 31 2014 4 1 2014 4 8 6 0 2014 4 8 6 0 2014 7 6 6 0 ppublish 24704024 S0378-1119(14)00397-7 10.1016/j.gene.2014.03.059 24691704 2014 04 23

1432-0738 88 5 2014 May Arch. Toxicol. Genotoxic and epigenetic mechanisms in arsenic carcinogenicity. 1043-67 10.1007/s00204-014-1233-7 Arsenic is a human carcinogen with weak mutagenic properties that induces tumors through mechanisms not yet completely understood. People worldwide are exposed to arsenic-contaminated drinking water, and epidemiological studies showed a high percentage of lung, bladder, liver, and kidney cancer in these populations. Several mechanisms by which arsenical compounds induce tumorigenesis were proposed including genotoxic damage and chromosomal abnormalities. Over the past decade, a growing body of evidence indicated that epigenetic modifications have a role in arsenic-inducing adverse effects on human health. The main epigenetic mechanisms are DNA methylation in gene promoter regions that regulate gene expression, histone tail modifications that regulate the accessibility of transcriptional machinery to genes, and microRNA activity (noncoding RNA able to modulate mRNA translation). The "double capacity" of arsenic to induce mutations and epimutations could be the main cause of arsenic-induced carcinogenesis. The aim of this review is to better clarify the mechanisms of the initiation and/or the promotion of arsenic-induced carcinogenesis in order to understand the best way to perform an early diagnosis and a prompt prevention that is the key point for protecting arsenic-exposed population. Studies on arsenic-exposed population should be designed in order to examine more comprehensively the presence and consequences of these genetic/epigenetic alterations. Bustaffa Elisa E Unit of Environmental Epidemiology and Diseases Registries, Institute of Clinical Physiology, National Council of Research, Via Moruzzi 1, 56123, Pisa, Italy. Stoccoro Andrea A Bianchi Fabrizio F Migliore Lucia L eng Journal Article Research Support, Non-U.S. Gov't 2014 04 02

Germany Arch Toxicol 0417615 0340-5761 IM 2013 12 5 2014 3 18 2014 4 2 2014 4 3 6 0 2014 4 3 6 0 2014 4 3 6 0 ppublish 10.1007/s00204-014-1233-7 24691704 24667374 2014 03 26

1937-9145 7 318 2014 Mar 25 Sci Signal MicroRNA circuits regulate the cancer-inflammation link. pe8 10.1126/scisignal.2005053 Genetic and epigenetic perturbations are required to transform normal cells into cancer cells. Inflammatory signaling pathways are activated in various cancers, linking chronic inflammation to oncogenesis. However, the molecular circuits that result in sustained activation of these inflammatory factors are not yet well understood. In the 28 January 2014 issue of Science Signaling, Xiang et al. identified a microRNA-mediated anti-inflammatory circuit that is repressed epigenetically in receptor-negative breast cancers. A high-throughput screen for signal transducer and activator of transcription 3 (STAT3)-regulated microRNAs revealed microRNA miR-146b as a direct STAT3 target in mammary epithelial cells, but DNA methylation in its promoter area suppressed miR-146b expression in cancer cells. Overexpression of miR-146b suppressed nuclear factor κB (NF-κB)-dependent expression of IL6 and subsequent STAT3 activation and decreased the STAT3-induced invasiveness and mesenchymal phenotype of breast cancer cells. Overall, this study contributes to our understanding of how inflammation is involved in oncogenic transformation. Further studies could evaluate the therapeutic potential of targeting this circuit in estrogen receptor-negative breast cancers. Iliopoulos Dimitrios D Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA. eng Comment Journal Article Research Support, Non-U.S. Gov't 2014 03 25

United States Sci Signal 101465400 IM Sci Signal. 2014;7(310):ra11 24473196 2014 3 27 6 0 2014 3 29 6 0 2014 3 29 6 0 epublish 7/318/pe8 10.1126/scisignal.2005053 24667374 24662924 2014 03 25 2014 03 25 2014 06 02

2157-9024 3 2014 Oncogenesis Frequent MYC coamplification and DNA hypomethylation of multiple genes on 8q in 8p11-p12-amplified breast carcinomas. e95 10.1038/oncsis.2014.8 Genetic and epigenetic (DNA methylation, histone modifications, microRNA expression) crosstalk promotes inactivation of tumor suppressor genes or activation of oncogenes by gene loss/hypermethylation or duplications/hypomethylation, respectively. The 8p11-p12 chromosomal region is a hotspot for genomic aberrations (chromosomal rearrangements, amplifications and deletions) in several cancer forms, including breast carcinoma where amplification has been associated with increased proliferation rates and reduced patient survival. Here, an integrative genomics screen (DNA copy number, transcriptional and DNA methylation profiling) performed in 229 primary invasive breast carcinomas identified substantial coamplification of the 8p11-p12 genomic region and the MYC oncogene (8q24.21), as well as aberrant methylation and transcriptional patterns for several genes spanning the 8q12.1-q24.22 genomic region (ENPP2, FABP5, IMPAD1, NDRG1, PLEKHF2, RRM2B, SQLE, TAF2, TATDN1, TRPS1, VPS13B). Taken together, our findings suggest that MYC activity and aberrant DNA methylation may also have a pivotal role in the aggressive tumor phenotype frequently observed in breast carcinomas harboring 8p11-p12 regional amplification. Parris T Z TZ Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Kovács A A Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden. Hajizadeh S S Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden. Nemes S S 1] Division of Clinical Cancer Epidemiology, Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, Gothenburg, Sweden [2] Department of Oncology, Regional Cancer Center (West), Western Sweden Health Care Region, Sahlgrenska University Hospital, Gothenburg, Sweden. Semaan M M Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Levin M M Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Karlsson P P Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. Helou K K Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Cancer Center, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. eng Journal Article 2014 03 24

United States Oncogenesis 101580004 2157-9024 PMC4038389 2013 12 10 2014 1 22 2014 1 27 2014 3 26 6 0 2014 3 26 6 0 2014 3 26 6 1 epublish oncsis20148 10.1038/oncsis.2014.8 24662924 PMC4038389 24641221 2014 10 14

1873-4286 20 38 2014 Curr. Pharm. Des. Editorial: disease control and active and healthy ageing: new paradigms of therapeutic strategy. 5919-20 Worldwide, the percentage of people aged over 60 years is growing up quicker than any other age group, as a result of both longer life expectancy and declining birth rates as well as a success of the public health policies and the socioeconomic development. The World Health Organization (WHO) has been pointed out recently that: "currently, one in every nine people in the world is 60 years of age or older. This is expected to increase to one in five people by 2050". This success (the transition to a much older population) is a challenge for the modern society that shall maximize the health and the functional ability of older people as well as their social participation and safety to achieve an "active ageing". "Health" refers to physical, mental and social well being as expressed in the WHO definition of health: "maintaining autonomy and independence for the older people is a key goal in the policy framework for active ageing". "Active" refers to "continuing participation in social, economic, cultural, spiritual and civic affairs, not just the ability to be physically active or to participate in the labour force". In this issue Alzetta et al. (University of Genoa, Italy) reviews the grounds and patterns of the structuring of longevity and ageing in our society [1]. The older people, even in poor countries, die of non-communicable diseases (NCDs), such as heart disease, cancer or diabetes, rather than of infectious or parasitic diseases. On 2010, the UN General Assembly passed the resolution A/RES/64/265NCD recognizing "the enormous human suffering, premature death and the seriously negative socioeconomic impact caused by the growing burden of NCD" and called for "global and national action at the highest level to address this development issue". In this special issue Bousquet et al. (Inserm, France) review the complexity of NCDs intertwined with ageing, show an overview of the problem and propose practical examples of System Medicine (SM) applied to NCDs [2]. Moreover, Cesario et al. (IRCCS "San Raffaele Pisana", Italy) review the novel system approaches to NCDs, discuss the passage from System Biology (SM) to SM and present the scientific and clinical background of a SM platform [3]. In this issue different pathologies, clinical conditions and pharmacological approaches are reviewed considering the role of ageing. Mazzucco et al. (Catholic University, Italy) review breast cancer in various age-groups and the response to Trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor [4]. Piotrowicz et al. (Jagiellonian University, Poland) review the pharmacological management of hypertension [5], Matera et al. (Second University of Naples) propose new treatment for chronic obstructive pulmonary disease (COPD) [6], and Zanandrea et al. (University of Toulose, France) review the treatment of sarcopenia [7]. As the population ages, the burden of neurodegenerative disorders, including Alzheimer disease (AD), will increase creating an unsustainable healthcare challenge due to a lack of effective treatment. In this issue Hasnain and Vieweg (Memorial University of Newfoundland, Canada) overview the vascular risk factors in AD and vascular dementia [8]. AD is characterized by disturbance of various high pre- and cortical functions. Cholinergic projections innervate the prefrontal cortex and reduced cholinergic function is associated with cognitive deficits. Cholinergic neurons are specific neurons that synthesize and release acetylcholine (ACh). ACh acts at nicotinic receptors (nAChR) and muscarinic receptors (mAChR). U.S. Food and Drug Administration (FDA) and The European Medicines Agency (EMA) approved several prescription drugs to treat people who have been diagnosed with AD. The drugs include: Razadyne® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil). These drugs target acetylcholinesterase (defined acetylcholinesterase inhibitors: AChEI) and, in principle, elevate cholinergic signaling. Another drug is known as Namenda® (Memantine), an N-methyl D-aspartate (NMDA) antagonist. None of these medications stops the disease itself: they help to maintain thinking, memory, and speaking skills but don't influence the disease' progression. Unfortunately these drugs are effective only for some patients, and may help only for a limited period of time. In this issue different authors describe new pharmacological approaches to neurodegenerative diseases beyond AChEI. Russo et al. (IRCCS "San Raffaele Pisana", Italy) in this issue describe the neurobiology of the α7-nAChR, its role in cognition and in AD, and the clinical status of the most promising molecules for the treatment of cognitive dysfunction in AD [9]. MicroRNA (miRNA), single-stranded RNA molecules consisting of 21-23 nucleotides, are post-transcriptional regulators of gene expression. Impaired miRNA levels are considered causally involved in many diseases, including neurodegenerative and psychiatric disorders. In this issue Greenberg and Soreq (Hebrew University, Israel) outline the current "state of the art" regarding miRNA regulation in neuropathology and explore the possibilities of the development of miRNA as therapeutics for neurodegenerative diseases [10]. Many neurodegenerative diseases may be referred as misfolding diseases Cardinale et al. (IRCCS "San Raffaele Pisana", Italy) review the ability of intrabodies to recognize misfolding and discuss the use of intrabodies against neurodegenerative disorders [11]. Chronic pain is a widespread problem affecting elder people, in this issue Taylor et al. (NEMA Research, USA) review the association between pain and obesity [12] and Del Bufalo et al. (IRCCS "San Raffaele Pisana", Italy) review the background, findings, implications and problems in using compounds that act on α9α10-nAChR as potential target in the pathophysiology of chronic pain [13]. As well-known, ageing is a complex process resulting by the interaction between genetic, environmental/behavioral (such as smoking, diet, use of medication, occupational diseases), epigenetic (alterations in DNA methylation patterns, posttranslational modification of histones, and chromatin remodeling), and purely stochastic factors. The time-dependent accumulation of cellular damage is widely considered to be the general cause of ageing. Nine candidate hallmarks, that contribute to the ageing process and collectively determine the ageing phenotype, has been described recently. The conceptualizations of the hallmarks of ageing, as for the conceptualizations of the hallmarks of cancer, may offer an organizing principle to effort and rationalize the complexities of ageing (phenotypes and genotypes). In this issue Jylhava (University of Tampere, Finland) reviews the genetic component of human longevity and its phenotypic effectors and discuss several rejuvenation strategies [13]. Capuron et al. (University Victor Segalen, France) review the role of immune system and inflammation in ageing [14]. "Frailty" is considered "a practical, unifying notion in the care of elderly patients that directs attention away from organ-specific diagnoses towards a more holistic viewpoint of the patient and their predicament". Due to the increasing probability to develop chronic diseases with age, elderly are the main user group of drugs. Moreover, multiple co-occurring medical conditions enhance the complexity generating important therapeutic needs that in turn require drug optimal characterization (i.e. safety and efficacy) as well as appropriately prescription and use and compliance monitoring [discussed in references 2-6]. The term "geriatric drug therapy" explains well the whole value chain from the product development to utilization of the product by the patient itself. Interdisciplinary studies and integrated assessments are needed to deep understand the manifold sources of patient complexity and their interactions, and how provision of healthcare should be harmonized with complexity to optimize health [discussed in 2-3]. Better health promotion and disease prevention interventions will make a significant contribution to the sustainability of health and care systems. 'Omics' research (including genomics, epi-genomics, metagenomics, metabolomics and proteomics) allows the resolution of cell biological processes to "an exceptional high definition" that poses the challenge to determine "when" and "how" the "omics" information may be applied (public/private sectors) to develop personalized/stratified approach in health promotion, diseases prevention and diseases cure. Systems (bio, pharmacology) medicine approaches have the potential to tackle this complexity trough an integration of a variety of medical research and computational modeling. Passing from reductionism to a system-oriented perspective, medical research will take advantage of these highthroughput technologies unveiling their full potential [reviewed in 2-3]. An ageing population will have a strong upward impact on public spending for long term care. This is because frailty and disability rise sharply at older ages, especially amongst the very old (aged 80+) which will be the fastest growing segment of the population in the coming decades. According to the " Ageing Working Group (AWG) reference scenario" based on current policy settings, public spending on longterm care is projected to double, increasing from 1.2% of GDP (gross domestic product) in 2007 to 2.3% of GDP in 2060 in the EU as a whole. In the conclusions of this issue Cesario et al. (ABSTRACT TRUNCATED) Russo Patrizia P Fini Massimo M Cesario Alfredo A Laboratory of Systems Approaches and Non Communicable Diseases, IRCCS "San Raffaele Pisana" Via di Valcannuta, 247, I-00166 Rome, Italy. patrizia_russo@hotmail.it. eng Journal Article

Netherlands Curr Pharm Des 9602487 1381-6128 IM 2014 3 20 6 0 2014 3 20 6 0 2014 3 20 6 0 ppublish CPD-EPUB-59661 24641221 24632304 2014 3 17 2014 11 5

1477-4054 2014 Mar 13 Brief. Bioinformatics Combining multidimensional genomic measurements for predicting cancer prognosis: observations from TCGA. With accumulating research on the interconnections among different types of genomic regulations, researchers have found that multidimensional genomic studies outperform one-dimensional studies in multiple aspects. Among many sources of multidimensional genomic data, The Cancer Genome Atlas (TCGA) provides the public with comprehensive profiling data on >30 cancer types, making it an ideal test bed for conducting and comparing different analyses. In this article, the analysis goal is to apply several existing methods and associate multidimensional genomic measurements with cancer outcomes in particular prognosis, with special focus on the predictive power of genomic signatures. We exploit clinical data and four types of genomic measurement including mRNA gene expression, DNA methylation, microRNA and copy number alterations for breast invasive carcinoma, glioblastoma multiforme, acute myeloid leukemia and lung squamous cell carcinoma collected by TCGA. To accommodate the high dimensionality, we extract important features using Principal Component Analysis, Partial Least Squares and Least Absolute Shrinkage and Selection Operator (Lasso), which are representative of dimension reduction and variable selection techniques and have been extensively adopted, and fit Cox survival models with combined important features. We calibrate the predictive power of each type of genomic measurement for the prognosis of four cancer types and find that the results vary across cancers. Our analysis also suggests that for most of the cancers in our study and the adopted methods, there is no substantial improvement in prediction when adding other genomic measurement after gene expression and clinical covariates have been included in the model. This is consistent with the findings that molecular features measured at the transcription level affect clinical outcomes more directly than those measured at the DNA/epigenetic level. Zhao Qing Q Shi Xingjie X Xie Yang Y Huang Jian J Shia Benchang B Ma Shuangge S ENG R03 CA182984 CA NCI NIH HHS United States JOURNAL ARTICLE 2014 3 13

Brief Bioinform 100912837 1467-5463 The Cancer Genome Atlas (TCGA) cancer prognosis multidimensional genomic study prediction 2014 3 18 6 0 2014 3 19 6 0 2014 3 19 6 0 aheadofprint bbu003 10.1093/bib/bbu003 24632304 24573597 2014 03 03 2014 10 28

1791-2431 31 4 2014 Apr Oncol. Rep. Diverse roles of miR-29 in cancer (review). 1509-16 10.3892/or.2014.3036 microRNAs (miRNAs) are non-coding RNAs which have the capacity to regulate gene expression at the post-transcriptional level, and have emerging as key factors involved in cancer at all stages ranging from initiation to metastasis. In the present review, we summmarize the diverse roles of the microRNA-29 (miR-29) family in cancer. First, we present a concise introduction to the miR-29 family and the expression profile of miR-29 in various cancer types. We next highlight the upstream regulatory pathway of miR-29 and describe the relationship between miR-29 and cancer in detail. As a tumor suppressor, miR-29 restrains cancer progression by promoting tumor cell apoptosis, by suppressing DNA methylation of tumor-suppressor genes, by reducing proliferation of tumors and by increasing chemosensitivity. However, as a tumor promoter, miR-29 mediates epithelial-mesenchymal transition (EMT) and promotes metastasis in breast cancer and colon cancer. Finally, we suggest that miR-29 represents a novel diagnostic and prognostic biomarker or a therapeutic target for cancer. Our review highlights the diverse relationship between miR-29 and cancer (particularly digestive system neoplasms). Further research of miR-29 in cancer is warranted. Jiang Hesong H Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu 210093, P.R. China. Zhang Guang G Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu 210093, P.R. China. Wu Jun-Hua JH Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu 210093, P.R. China. Jiang Chun-Ping CP Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital, Medical School, Nanjing University, Nanjing, Jiangsu 210008, P.R. China. eng Journal Article Research Support, Non-U.S. Gov't Review 2014 02 20

Greece Oncol Rep 9422756 1021-335X 0 MIRN29 microRNA, human 0 MicroRNAs IM Animals Humans MicroRNAs genetics Neoplasms genetics 2013 12 09 2014 1 17 2014 2 20 2014 2 28 6 0 2014 2 28 6 0 2014 10 29 6 0 ppublish 10.3892/or.2014.3036 24573597 24521265 2014 02 13

1752-0509 7 Suppl 3 2013 BMC Syst Biol Intra-relation reconstruction from inter-relation: miRNA to gene expression. S8 10.1186/1752-0509-7-S3-S8 In computational biology, a novel knowledge has been obtained mostly by identifying 'intra-relation,' the relation between entities on a specific biological level such as from gene expression or from microRNA (miRNA) and many such researches have been successful. However, intra-relations are not fully explaining complex cancer mechanisms because the inter-relation information between different levels of genomic data is missing, e.g. miRNA and its target genes. The 'inter-relation' between different levels of genomic data can be constructed from biological experimental data as well as genomic knowledge. Previously, we have proposed a graph-based framework that integrates with multi-layers of genomic data, copy number alteration, DNA methylation, gene expression, and miRNA expression, for the cancer clinical outcome prediction. However, the limitation of previous work was that we integrated with multi-layers of genomic data without considering of inter-relationship information between genomic features. In this paper, we propose a new integrative framework that combines genomic dataset from gene expression and genomic knowledge from inter-relation between miRNA and gene expression for the clinical outcome prediction as a pilot study. In order to demonstrate the validity of the proposed method, the prediction of short-term/long-term survival for 82 patients in glioblastoma multiforme (GBM) was adopted as a base task. Based on our results, the accuracy of our predictive model increases because of incorporation of information fused over genomic dataset from gene expression and genomic knowledge from inter-relation between miRNA and gene expression. In the present study, the intra-relation of gene expression was reconstructed from inter-relation between miRNA and gene expression for prediction of short-term/long-term survival of GBM patients. Our finding suggests that the utilization of external knowledge representing miRNA-mediated regulation of gene expression is substantially useful for elucidating the cancer phenotype. Kim Dokyoon D Shin Hyunjung H Joung Je-Gun JG Lee Su-Yeon SY Kim Ju Han JH eng Journal Article Research Support, Non-U.S. Gov't 2013 10 16

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1432-0878 356 3 2014 Jun Cell Tissue Res. Aberrant DNA methylation of microRNA genes in human breast cancer - a critical appraisal. 657-64 10.1007/s00441-014-1793-0 Aberrant DNA methylation of regulatory sequences is a well-documented mechanism of functional deletion of genes with anti-tumourigenic properties including microRNAs. This review discusses the publications describing aberrant methylation of microRNA genes in human breast cancer cells. Among the anti-tumourigenic properties of epigenetically inactivated microRNA genes, the inhibition of proliferation and of epithelial-to-mesenchymal transition (EMT) are the best studied. Several studies are conceptually very interesting and present a comprehensive functional characterization of anti-tumorigenic microRNAs. The link between microRNA expression and gene methylation is not addressed directly by all studies and a number of studies are limited in their strength by not including primary breast cancer specimens or by analysing very small sets of primary human specimens. The publications cover a wide range of DNA methylation detection techniques, often making direct comparison of results challenging. Despite the identification and thorough characterization of many interesting candidates and functionally important microRNA genes affected by DNA methylation, the translation of microRNA gene methylation as a new biomarker into the daily routine practice has not yet worked out. Lehmann Ulrich U Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Germany, Lehmann.Ulrich@MH-Hannover.de. eng Journal Article 2014 02 09

Germany Cell Tissue Res 0417625 0302-766X IM 2013 11 13 2014 1 2 2014 2 9 2014 2 11 6 0 2014 2 11 6 0 2014 2 11 6 0 ppublish 10.1007/s00441-014-1793-0 24509818 24504368 2014 03 19 2014 07 15

1532-1827 110 6 2014 Mar 18 Br. J. Cancer Genistein downregulates onco-miR-1260b and upregulates sFRP1 and Smad4 via demethylation and histone modification in prostate cancer cells. 1645-54 10.1038/bjc.2014.48 Recently several microRNAs (miRNAs) have been found to be regulated by genistein in cancer cells. In this study, we focused on the gene regulatory effect of genistein on microRNA and its target genes in prostate cancer (PC). Initially, we investigated the effect of genistein on prostate cancer cells and identified that the expression of miRNA-1260b was decreased by genistein. We performed functional analyses and investigated the relationship between miRNA-1260b expression and prostate cancer patient outcomes. Two target genes (sFRP1 and Smad4) of miR-1260b were identified based on computer algorithm and 3'UTR luciferase assay was carried out to determine direct miRNA regulation of the genes. Genistein promoted apoptosis while inhibiting prostate cancer cell proliferation, invasion and TCF reporter activity in PC cells. MiR-1260b was highly expressed in prostate cancer tissues and significantly downregulated by genistein in PC cells. After knocking down miR-1260b, cell proliferation, invasion, migration and TCF reporter activity were decreased in PC cells. Western analysis and 3'UTR luciferase assay showed that the two target genes (sFRP1 and Smad4) were directly regulated by miR-1260b. The expression of sFRP1 and Smad4 was significantly decreased in prostate cancer tissues. Genistein also increased expression of these two genes via DNA demethylation and histone modifications. Our data suggest that genistein exerts its anti-tumour effect via downregulation of miR-1260b that targeted sRRP1 and Smad4 genes in prostate cancer cells. The expression of sFRP1 and Smad4 was also modulated by genistein via DNA methylation or histone modifications in PC cell lines. Hirata H H Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. Hinoda Y Y Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan. Shahryari V V Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. Deng G G Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. Tanaka Y Y Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. Tabatabai Z L ZL Department of Pathology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. Dahiya R R Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, California, USA. eng I01BX001123 BX BLRD VA United States R01CA130860 CA NCI NIH HHS United States R01CA138642 CA NCI NIH HHS United States R01CA160079 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2014 02 06

England Br J Cancer 0370635 0007-0920 0 Anticarcinogenic Agents 0 Histones 0 MIRN1260 microRNA, human 0 MicroRNAs 0 SMAD4 protein, human 0 Smad4 Protein DH2M523P0H Genistein EC 2.7.11.1 ATR protein, human EC 2.7.11.1 Ataxia Telangiectasia Mutated Proteins IM Anticarcinogenic Agents pharmacology Ataxia Telangiectasia Mutated Proteins biosynthesis genetics metabolism DNA Methylation drug effects Down-Regulation Gene Expression Regulation, Neoplastic drug effects Genistein pharmacology Histones genetics metabolism Humans In Situ Hybridization, Fluorescence Male MicroRNAs genetics metabolism Prostatic Neoplasms drug therapy genetics metabolism pathology Smad4 Protein biosynthesis genetics metabolism Tissue Array Analysis Up-Regulation drug effects PMC3960620 [Available on 03/18/15] 2013 11 14 2014 1 6 2014 1 8 2014 2 06 2014 2 8 6 0 2014 2 8 6 0 2014 7 16 6 0 2015 3 18 0 0 ppublish bjc201448 10.1038/bjc.2014.48 24504368 PMC3960620 24499724 2014 04 18

1559-2308 9 4 2014 Apr Epigenetics Overexpression of MYC and EZH2 cooperates to epigenetically silence MST1 expression. 634-43 10.4161/epi.27957 Hippo-like MST1 protein kinase regulates cell growth, organ size, and carcinogenesis. Reduction or loss of MST1 expression is implicated in poor cancer prognosis. However, the mechanism leading to MST1 silencing remains elusive. Here, we report that both MYC and EZH2 function as potent suppressors of MST1 expression in human prostate cancer cells. We demonstrated that concurrent overexpression of MYC and EZH2 correlated with the reduction or loss of MST1 expression, as shown by RT-qPCR and immunoblotting. Methylation sensitive PCR and bisulfite genomic DNA sequencing showed that DNA methylation caused MST1 silencing. Pharmacologic and RNAi experiments revealed that MYC and EZH2 silenced MST1 expression by inhibiting its promoter activity, and that EZH2 was a mediator of the MYC-induced silencing of MST1. In addition, MYC contributed to MST1 silencing by partly inhibiting the expression of microRNA-26a/b, a negative regulator of EZH2. As shown by ChIP assays, EZH2-induced DNA methylation and H3K27me3 modification, which was accompanied by a reduced H3K4me3 mark and RNA polymerase II occupancy on the MST1 promoter CpG region, were the underlying cause of MST1 silencing. Moreover, potent pharmacologic inhibitors of MYC or EZH2 suppressed prostate cancer cell growth in vitro, and the knockdown of MST1 caused cells' resistance to MYC and EZH2 inhibitor-induced growth retardation. These findings indicate that MYC, in concert with EZH2, epigenetically attenuates MST1 expression and suggest that the loss of MST1/Hippo functions is critical for the MYC or EZH2 mediation of cancer cell survival. Kuser-Abali Gamze G Department of Medicine, Division of Hematology and Oncology; Biomedical Sciences, Division of Cancer Biology and Therapeutics; The Uro-Oncology Program; Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles, CA USA. Alptekin Ahmet A Department of Medicine, Division of Hematology and Oncology; Biomedical Sciences, Division of Cancer Biology and Therapeutics; The Uro-Oncology Program; Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles, CA USA. Cinar Bekir B Department of Medicine, Division of Hematology and Oncology; Biomedical Sciences, Division of Cancer Biology and Therapeutics; The Uro-Oncology Program; Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles, CA USA; Department of Medicine; David Geffen School of Medicine; University of California Los Angeles; Los Angeles, CA USA. eng Journal Article Research Support, Non-U.S. Gov't 2014 02 27

United States Epigenetics 101265293 1559-2294 IM PMC4121373 [Available on 04/01/15] DNA methylation EZH2 and MST1/Hippo H3K27me3 MYC epigenetics 2014 2 27 2014 2 7 6 0 2014 2 7 6 0 2014 2 7 6 0 2015 4 1 0 0 ppublish 24499724 27957 10.4161/epi.27957 PMC4121373 24498243 2014 02 05 2014 10 15

1932-6203 9 1 2014 PLoS ONE MicroRNA-10a is down-regulated by DNA methylation and functions as a tumor suppressor in gastric cancer cells. e88057 10.1371/journal.pone.0088057 MicroRNAs act as posttranscriptional regulators of gene expression in many biological processes. Their deregulations occur commonly in gastric cancer (GC). Although DNA methylation constitutes an important mechanism for microRNA deregulation in cancer, this field largely remains unexplored. Total RNA was extracted from the tissues of 100 patients with GC and four gastric cancer cell lines. The expression levels of miR-10a were determined by real-time PCR with specific TaqMan probes. Moreover, a functional analysis of miR-10a in regulating cell proliferation, migration and invasion was performed. Subsequently, quantitative methylation-specific PCR (qMSP) was used to detect the DNA methylation status in the CpG islands upstream of miR-10a. In this study, we found that the expression of miR-10a in GC cells was lower than that in normal cells, which was due to the hypermethylation of the CpG islands upstream of miR-10a. We also validated the slightly lower expression of miR-10a in GC tissues than their adjacent non-neoplastic tissues in 100 GC patients and confirmed the hypermethylation of CpG islands upstream of miR-10a in some patients. Furthermore, re-introduction of miR-10a into GC cells was able to inhibit cell proliferation, migration and invasion. Bioinformatic and immunoblot analysis indicated that the tumor suppressor roles of miR-10a in GC cells were possibly through targeting HOXA1. Our data indicate that miR-10a acts as a tumor suppressor in GC cells and is partially silenced by DNA hypermethylation in GC, suggesting that miR-10a may serve as a potential diagnostic or therapeutic target of GC. Jia Hongyan H Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan, PR China. Zhang Zhengyi Z Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Zou Dongling D Department of Gynecologic Oncology, Chongqing Cancer Institute, Chongqing, PR China. Wang Bin B Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China ; Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan, PR China. Yan Yunmeng Y Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Luo Min M Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Dong Lei L Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Yin Haixin H Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China ; Department of Surgery, The First Hospital of Shanxi Medical University, Taiyuan, PR China. Gong Bei B Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Li Zheng Z Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Wang Fang F Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Song Wei W Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Liu Changzheng C Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Ma Yanni Y Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Zhang Junwu J Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. Zhao Haoliang H Department of Surgery,The Shanxi Academy of Medical Sciences & Shanxi Dayi Hospital, Taiyuan, PR China. Li Jianxiong J Cancer center, The General Hospital of the People's Liberation Army, Beijing, PR China. Yu Jia J Department of Biochemistry, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, PR China. eng Clinical Trial Journal Article Multicenter Study Research Support, Non-U.S. Gov't 2014 01 31

United States PLoS One 101285081 1932-6203 0 DNA, Neoplasm 0 MIRN10 microRNA, human 0 MicroRNAs 0 RNA, Neoplasm IM Cancer Lett. 2010 Dec 1;298(1):50-63 20619534 Epigenetics. 2011 Jun;6(6):740-51 21562367 Cancer. 2011 Jul 1;117(13):2842-52 21692045 Clin Sci (Lond). 2011 Nov;121(10):437-47 21658006 J Cell Sci. 2011 Sep 1;124(Pt 17):2997-3005 21878506 BMC Cancer. 2012;12:146 22498108 Ann Surg Oncol. 2012 Jul;19(7):2394-402 22407312 Cancer Lett. 2012 Nov 28;324(2):186-96 22634495 Oncogene. 2011 Jun 9;30(23):2644-58 21358675 BMC Cancer. 2002 Dec 26;2:36 12502433 Nature. 2004 May 27;429(6990):457-63 15164071 Cell. 2005 Jan 14;120(1):15-20 15652477 Nat Rev Genet. 2005 Dec;6(12):893-904 16341070 Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5078-83 16549775 Cancer Res. 2007 Nov 1;67(21):10117-22 17974952 Cancer Res. 2008 Apr 1;68(7):2094-105 18381414 Hepatology. 2008 Apr;47(4):1223-32 18307259 Blood. 2008 May 15;111(10):5078-85 18337557 RNA. 2008 Nov;14(11):2348-60 18812439 Mol Cancer Res. 2008 Dec;6(12):1830-40 19074828 Clin Cancer Res. 2010 Feb 15;16(4):1129-39 20145181 Carcinogenesis. 2010 May;31(5):777-84 20080834 Cancer Res. 2010 Aug 15;70(16):6609-18 20682795 Cell Line, Tumor Cell Movement Cell Proliferation DNA Methylation DNA, Neoplasm metabolism Down-Regulation Female Gene Expression Regulation, Neoplastic Humans Male MicroRNAs biosynthesis RNA, Neoplasm biosynthesis Stomach Neoplasms metabolism pathology PMC3909310 2014 2013 1 26 2014 1 4 2014 1 31 2014 2 6 6 0 2014 2 6 6 0 2014 10 16 6 0 epublish 10.1371/journal.pone.0088057 PONE-D-13-04978 24498243 PMC3909310 24486548 2014 02 24 2014 04 22

1090-2104 444 4 2014 Feb 21 Biochem. Biophys. Res. Commun. Epigenetic silencing of MicroRNA-503 regulates FANCA expression in non-small cell lung cancer cell. 611-6 10.1016/j.bbrc.2014.01.103 S0006-291X(14)00136-3 It is reported that MicroRNA-503 (miR-503) regulates cell apoptosis, and thus modulates the resistance of non-small cell lung cancer cells (NSCLC) to cisplatin. However, the exact role of miR-503 in NSCLC remains unknown. In the present study, the level of miR-503 expression in NSCLC was evaluated using realtime PCR, and the DNA methylation status within miR-503 promoter was analyzed by Combined Bisulfite Restriction Analysis (COBRA) or bisulfite-treated DNA sequencing assays (BSP). We found that the expression of miR-503 was significantly decreased in NSCLC tissues compared to normal tissues. A statistically significant inverse association was found between miR-503 methylation status and expression of the miR-503 in tumor tissues (P<0.001), and expression of miR-503 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that methylation was associated with the transcriptional silencing. Then, we show that miR-503 targets a homologous DNA region in the 3'-UTR region of the Fanconi anemia complementation group A protein (FANCA) gene and represses its expression at the transcriptional level. Taken together, our results suggest that miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin at least in part by targeting FANCA. Copyright © 2014 Elsevier Inc. All rights reserved. Li Ning N Department of Respiratory Medicine, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China. Zhang Fangfang F Department of Internal Medicine-Oncology, The First Affiliated Hospital, Zhengzhou University, China. Li Suyun S Department of Respiratory Medicine, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China. Electronic address: lisuyuntcm@163.com. Zhou Suzhen S Department of Respiratory Medicine, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou 450000, China. eng Journal Article 2014 01 31

United States Biochem Biophys Res Commun 0372516 0006-291X 0 Antineoplastic Agents 0 Fanconi Anemia Complementation Group A Protein 0 MIRN503 microRNA, human 0 MicroRNAs Q20Q21Q62J Cisplatin IM Antineoplastic Agents administration & dosage therapeutic use Base Sequence Carcinoma, Non-Small-Cell Lung drug therapy genetics pathology Cell Line, Tumor Cisplatin administration & dosage therapeutic use DNA Methylation drug effects Fanconi Anemia Complementation Group A Protein genetics Gene Expression Regulation, Neoplastic Gene Silencing Humans Lung drug effects metabolism pathology Lung Neoplasms drug therapy genetics pathology MicroRNAs genetics FANCA Methylation Non-small cell lung cancer cell miR-503 2014 1 19 2014 1 22 2014 1 31 2014 2 4 6 0 2014 2 4 6 0 2014 4 23 6 0 ppublish 24486548 S0006-291X(14)00136-3 10.1016/j.bbrc.2014.01.103 24464287 2014 02 28 2014 04 28

1548-7105 11 3 2014 Mar Nat. Methods Similarity network fusion for aggregating data types on a genomic scale. 333-7 10.1038/nmeth.2810 Recent technologies have made it cost-effective to collect diverse types of genome-wide data. Computational methods are needed to combine these data to create a comprehensive view of a given disease or a biological process. Similarity network fusion (SNF) solves this problem by constructing networks of samples (e.g., patients) for each available data type and then efficiently fusing these into one network that represents the full spectrum of underlying data. For example, to create a comprehensive view of a disease given a cohort of patients, SNF computes and fuses patient similarity networks obtained from each of their data types separately, taking advantage of the complementarity in the data. We used SNF to combine mRNA expression, DNA methylation and microRNA (miRNA) expression data for five cancer data sets. SNF substantially outperforms single data type analysis and established integrative approaches when identifying cancer subtypes and is effective for predicting survival. Wang Bo B 1] Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada. [2]. Mezlini Aziz M AM 1] Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada. [2] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. Demir Feyyaz F 1] Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada. [2] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. Fiume Marc M Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. Tu Zhuowen Z Department of Cognitive Science, University of California San Diego, San Diego, California, USA. Brudno Michael M 1] Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada. [2] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. Haibe-Kains Benjamin B 0000000276840079 1] Institut de Recherches Cliniques de Montréal, Université de Montréal, Montréal, Quebec, Canada. [2]. Goldenberg Anna A 1] Genetics and Genome Biology, SickKids Research Institute, Toronto, Ontario, Canada. [2] Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. eng Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2014 01 26

United States Nat Methods 101215604 1548-7091 IM Brain Neoplasms genetics Computational Biology methods Disease genetics Gene Regulatory Networks Genomics Glioblastoma genetics Humans Statistics as Topic methods 2013 5 08 2013 12 17 2014 1 26 2014 1 28 6 0 2014 1 28 6 0 2014 4 29 6 0 ppublish nmeth.2810 10.1038/nmeth.2810 24464287 24448385 2014 04 04

1555-8576 15 4 2014 Apr Cancer Biol. Ther. MicroRNA-148b and microRNA-152 reactivate tumor suppressor genes through suppression of DNA methyltransferase-1 gene in pancreatic cancer cell lines. 419-27 10.4161/cbt.27630 Overexpression of DNA methyltransferase 1 (DNMT-1) is observed mostly in pancreatic cancer and it can cause tumor suppressor genes silencing in this disease. Recent studies suggest that abnormal expressions of microRNAs (miRs) are involved in pathogenesis of different types of human cancers including pancreatic cancer. In this study we aimed to investigate the effect of miR-148b and -152 on reverting the tumorigenic phenotype of pancreatic cancer cell lines. In order to investigate whether miR-148b and -152 are involved in the regulation of DNMT-1, luciferase reporter assay was used and confirmed that the DNMT-1 mRNA could be a target for miR-148b and miR-152. Furthermore, overexpression of miR-148b and -152 in pancreatic cancer cell lines (MIA PaCa-2 and AsPC-1) decreased DNMT-1 expression (53% and 59% respectively), returned DNA methylation to normal patterns and induced re-expression of tumor suppressor genes, like BNIP3 (4.7- and 3.8-fold) and SPARC (5.3- and 2.9-fold) for miR-148b and -152 respectively. Moreover, the introduced miR-148b and -152 could inhibit the proliferation of MIA PaCa-2 (35% and 37% respectively) and AsPC-1 (39% and 40% respectively) cell lines. The apoptosis rates of MIA PaCa-1 after treatment with miR-148b and -152 were 10% and 8% respectively; while these rates in AsPC-1 were 16% and 11% respectively. Conclusively these findings mean that miRs that are targeting DNMT-1 and modifying methylation status of tumor suppressor genes such as BNIP3 and SPARC can be applied in killing the pancreatic cancer cells and decreasing the tumorigenicity of these cells. Azizi Masoumeh M Department of Molecular Medicine; Biotechnology Research Center; Pasteur Institute of Iran; Tehran, Iran. Teimoori-Toolabi Ladan L Department of Molecular Medicine; Biotechnology Research Center; Pasteur Institute of Iran; Tehran, Iran. Arzanani Mohsen Karimi MK Center for Hematology and Regenerative Medicine; Karolinska Institute Huddinge; Stockholm, Sweden. Azadmanesh Kayhan K Virology Department; Pasteur Institute of Iran; Tehran, Iran. Fard-Esfahani Pezhman P Department of Biochemistry; Pasteur Institute of Iran; Tehran, Iran. Zeinali Sirous S Department of Molecular Medicine; Biotechnology Research Center; Pasteur Institute of Iran; Tehran, Iran. eng Journal Article Research Support, Non-U.S. Gov't 2014 01 21

United States Cancer Biol Ther 101137842 1538-4047 IM PMC3979819 [Available on 04/01/15] DNMT1 methylation microRNAs pancreatic neoplasms tumor suppressor 2014 1 21 2014 1 23 6 0 2014 1 23 6 0 2014 1 23 6 0 2015 4 1 0 0 ppublish 24448385 27630 10.4161/cbt.27630 PMC3979819 24433955 2014 04 15 2014 05 29

1532-1967 40 5 2014 Jun Cancer Treat. Rev. Epigenetic targeting in pancreatic cancer. 656-64 10.1016/j.ctrv.2013.12.002 S0305-7372(13)00265-X The prognosis of pancreatic cancer patients is very poor, with a 5-year survival of less than 6%. Therefore, there is an urgent need for new therapeutic options in pancreatic cancer. In the past years it became evident that deregulation of epigenetic mechanisms plays an important role in pancreatic carcinogenesis. This review focuses on the exploitation of drugs that alter histone modifications, DNA methylation and microRNA expression as options for the treatment of pancreatic cancer. Copyright © 2014 Elsevier Ltd. All rights reserved. van Kampen Jasmijn G M JG Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Urology 267, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Jasmijn.vanKampen@radboudumc.nl. Marijnissen-van Zanten Monica A J MA Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Monica.vanZanten@radboudumc.nl. Simmer Femke F Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Femke.Doubrava-Simmer@radboudumc.nl. van der Graaf Winette T A WT Department of Medical Oncology 452, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Winette.vanderGraaf@radboudumc.nl. Ligtenberg Marjolijn J L MJ Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; Department of Human Genetics 855, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Marjolijn.Ligtenberg@radboudumc.nl. Nagtegaal Iris D ID Department of Pathology 824, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address: Iris.Nagtegaal@radboudumc.nl. eng Journal Article Review 2014 01 03

Netherlands Cancer Treat Rev 7502030 0305-7372 0 Antineoplastic Agents 0 Histone Deacetylase Inhibitors 0 MicroRNAs EC 2.1.1.- histone methyltransferase EC 2.1.1.43 Histone-Lysine N-Methyltransferase IM Antineoplastic Agents pharmacology therapeutic use Clinical Trials as Topic DNA Methylation drug effects genetics Epigenesis, Genetic drug effects genetics Female Forecasting Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors therapeutic use Histone-Lysine N-Methyltransferase antagonists & inhibitors therapeutic use Humans Male MicroRNAs drug effects genetics Molecular Targeted Therapy methods trends Pancreatic Neoplasms drug therapy genetics pathology Treatment Outcome Tumor Microenvironment drug effects DNA methyltransferase inhibitor Epigenetics Histone deacetylase inhibitor Histone methyltransferase inhibitor MicroRNA Pancreatic cancer Therapy 2013 10 10 2013 12 18 2013 12 21 2014 1 3 2014 1 18 6 0 2014 1 18 6 0 2014 5 30 6 0 ppublish 24433955 S0305-7372(13)00265-X 10.1016/j.ctrv.2013.12.002 24385403 2014 05 23

1179-2000 18 3 2014 Jun Mol Diagn Ther Prognostic and predictive biomarkers: tools in personalized oncology. 273-84 10.1007/s40291-013-0077-9 Oncology indispensably leads us to personalized medicine, which allows an individual approach to be taken with each patient. Personalized oncology is based on pharmacogenomics and the effect of genetic differences in individuals (germline and somatic) on the way cancer patients respond to chemotherapeutics. Biomarkers detected using molecular biology tools allow the molecular characterization of cancer signatures and provide information relevant for personalized treatment. Biomarkers can be divided into two main subgroups: prognostic and predictive. The aim of the application of prognostic biomarkers, which provide information on the overall cancer outcome in patients, is to facilitate cancer diagnosis, usually with no need for putting invasive methods into use. Predictive biomarkers help to optimize therapy decisions, as they provide information on the likelihood of response to a given chemotherapeutic. Among the prognostic factors that identify patients with different outcome risks (e.g., recurrence of the disease), the following factors can be distinguished: somatic and germline mutations, changes in DNA methylation that lead to the enhancement or suppression of gene expression, the occurrence of elevated levels of microRNA (miRNA) capable of binding specific messenger RNA (mRNA) molecules, which affects gene expression, as well as the presence of circulating tumor cells (CTCs) in blood, which leads to a poor prognosis for the patient. Biomarkers for personalized oncology are used mainly in molecular diagnostics of chronic myeloid leukemia, colon, breast and lung cancer, and recently in melanoma. They are successfully used in the evaluation of the benefits that can be achieved through targeted therapy or in the evaluation of toxic effects of the chemotherapeutic used in the therapy. Nalejska Ewelina E Department of Thoracic Surgery and Tumors, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Nicolaus Copernicus University, Torun, Poland. Mączyńska Ewa E Lewandowska Marzena Anna MA eng Journal Article Research Support, Non-U.S. Gov't

New Zealand Mol Diagn Ther 101264260 1177-1062 IM Ann Oncol. 2008 Aug;19(8):1423-9 18407954 Nature. 2008 Oct 23;455(7216):1061-8 18772890 Nature. 2008 Oct 23;455(7216):1069-75 18948947 J Appl Genet. 2008;49(4):407-14 19029688 Neuroepidemiology. 2009;32(1):21-9 18997474 Cancer Res. 2008 Dec 15;68(24):10307-14 19074899 Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19893-7 19064915 Breast Cancer Res. 2008;10 Suppl 1:S2 19091006 PLoS One. 2008;3(12):e4003 19104657 Cancer Res. 2009 Mar 1;69(5):1851-7 19223544 N Engl J Med. 2000 Nov 9;343(19):1350-4 11070098 Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14608-13 11121063 Am J Hum Genet. 2001 Feb;68(2):420-31 11133358 N Engl J Med. 2001 May 3;344(18):1373-7 11333995 Clin Cancer Res. 2001 Sep;7(9):2832-9 11555601 Nature. 2002 Jan 31;415(6871):530-6 11823860 Nature. 2002 Jun 27;417(6892):949-54 12068308 Int J Cancer. 2002 Sep 20;101(3):253-8 12209976 N Engl J Med. 2003 Jul 17;349(3):247-57 12867608 Clin Cancer Res. 2004 Mar 15;10(6):1871-4 15041700 N Engl J Med. 2004 May 27;350(22):2239-46 15163773 N Engl J Med. 1988 Sep 1;319(9):525-32 2841597 Ann Intern Med. 1991 Oct 15;115(8):623-38 1716430 J Biol Chem. 1996 Jun 7;271(23):13916-24 8662860 J Clin Invest. 1996 Aug 1;98(3):610-5 8698850 Mol Cell Biol. 1997 Sep;17(9):5612-9 9271436 Cancer. 2009 Apr 15;115(8):1723-33 19170230 Nat Rev Cancer. 2009 Jul;9(7):489-99 19536109 Br J Cancer. 2009 Aug 18;101(4):715-21 19603018 Mol Cancer Ther. 2009 Aug;8(8):2152-62 19671734 Breast Cancer Res Treat. 2009 Oct;117(3):483-95 18819002 Jpn J Clin Oncol. 2009 Oct;39(10):651-6 19596663 Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6 19915144 Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2136-40 20080650 EMBO Mol Med. 2010 May;2(5):146-58 20432502 Breast Cancer Res. 2010;12(4):R64 20731819 PLoS One. 2012;7(11):e50587 23189206 J Transl Med. 2012;10:222 23146106 Br J Cancer. 2012 Dec 4;107(12):1987-96 23169280 Urol J. 2012 Fall;9(4):691-9 23235975 Neoplasma. 2013;60(2):135-42 23259781 Clin Chim Acta. 2013 Feb 1;416:5-10 23178446 Prostate Cancer Prostatic Dis. 2013 Mar;16(1):35-40 23165430 Int J Cancer. 2013 Jul;133(1):67-78 23280316 J Invest Dermatol. 2013 Jun;133(6):1460-2 23673501 Mol Diagn Ther. 2013 Jun;17(3):193-203 23606169 Neurology. 2013 Oct 22;81(17):1515-22 24068788 Mol Diagn Ther. 2014 Feb;18(1):45-53 23934769 J Clin Oncol. 1999 Sep;17(9):2745-51 10561349 Br J Cancer. 2000 Feb;82(4):913-23 10732766 Mol Cell Biol. 1997 Oct;17(10):5813-22 9315639 Cancer Res. 1999 Feb 15;59(4):793-7 10029064 N Engl J Med. 2005 Mar 10;352(10):997-1003 15758010 PLoS Med. 2005 Mar;2(3):e73 15737014 Mol Cancer. 2010;9:317 21172025 Br J Clin Pharmacol. 2011 May;71(5):737-50 21480951 N Engl J Med. 2011 Jun 30;364(26):2507-16 21639808 Nat Rev Endocrinol. 2011 Oct;7(10):569-80 21878896 Eur J Med Res. 2011 Oct 10;16(10):445-50 22024423 Ann Acad Med Singapore. 2011 Aug;40(8):362-8 22065002 J Clin Oncol. 2011 Nov 10;29(32):4279-85 21990395 Clin Cancer Res. 2011 Nov 15;17(22):7183-93 21976532 J Cancer Res Clin Oncol. 2012 Jan;138(1):153-61 22071603 BMC Med. 2011;9:133 22168215 Asian Pac J Cancer Prev. 2011;12(10):2629-35 22320965 J Neurooncol. 2012 May;108(1):11-27 22270850 BMC Cancer. 2012;12:78 22373240 Ginekol Pol. 2012 Apr;83(4):291-4 22712262 Lancet Oncol. 2012 Jul;13(7):688-95 22677156 Hum Genet. 2012 Oct;131(10):1627-38 22752797 J Zhejiang Univ Sci B. 2012 Sep;13(9):663-75 22949358 Ann Surg Oncol. 2012 Oct;19(10):3257-63 22965266 Clin Cancer Res. 2012 Oct 15;18(20):5682-9 22908099 PLoS One. 2012;7(9):e45802 23071848 BMC Med Genomics. 2012;5:40 22954303 BMC Cancer. 2012;12:243 22695491 Cancer Res. 2005 Nov 15;65(22):10199-207 16288007 Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):839-44 16467097 Cancer Res. 2006 Feb 15;66(4):2000-11 16488999 Eur J Cancer. 2006 Mar;42(5):582-8 16427778 J Clin Oncol. 2006 Sep 10;24(26):4340-6 16908931 N Engl J Med. 2006 Dec 7;355(23):2408-17 17151364 Nature. 2007 Mar 8;446(7132):153-8 17344846 Nature. 2007 Aug 2;448(7153):561-6 17625570 J Mol Diagn. 2007 Sep;9(4):464-71 17690212 J Clin Oncol. 2007 Sep 1;25(25):3837-45 17761971 Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7 18093943 Cancer Res. 2008 Jan 15;68(2):425-33 18199536 Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5 18227510 Cancer Res. 2008 Jun 15;68(12):4853-61 18559533 PMC4031398 2014 1 4 6 0 2014 1 5 6 0 2014 1 5 6 0 ppublish 10.1007/s40291-013-0077-9 24385403 PMC4031398 24382385 2014 01 02 2014 03 03

1558-8238 124 1 2014 Jan 2 J. Clin. Invest. Characterizing DNA methylation alterations from The Cancer Genome Atlas. 17-23 10.1172/JCI69740 69740 The Cancer Genome Atlas (TCGA) Research Network is an ambitious multi-institutional consortium effort aimed at characterizing sequence, copy number, gene (mRNA) expression, microRNA expression, and DNA methylation alterations in 30 cancer types. TCGA data have become an extraordinary resource for basic, translational, and clinical researchers and have the potential to shape cancer diagnostic and treatment strategies. DNA methylation changes are integral to all aspects of cancer genomics and have been shown to have important associations with gene expression, sequence, and copy number changes. This Review highlights the knowledge gained from DNA methylation alterations in human cancers from TCGA. Weisenberger Daniel J DJ eng Journal Article Review 2014 01 02

United States J Clin Invest 7802877 0021-9738 0 BRCA1 Protein 0 BRCA1 protein, human 0 Chromatin 0 Cyclin-Dependent Kinase Inhibitor p16 0 Tumor Suppressor Proteins EC 1.1.1.41 Isocitrate Dehydrogenase EC 2.1.1.- DNA Modification Methylases EC 2.1.1.63 MGMT protein, human EC 6.5.1.- DNA Repair Enzymes AIM IM Animals BRCA1 Protein genetics Chromatin genetics metabolism Cyclin-Dependent Kinase Inhibitor p16 genetics DNA Methylation DNA Modification Methylases physiology DNA Repair Enzymes physiology Epigenesis, Genetic Genome, Human Humans Isocitrate Dehydrogenase genetics Mutation Neoplasms enzymology genetics Tumor Suppressor Proteins physiology PMC3871233 [Available on 01/01/15] 2014 1 2 2014 1 2 2014 1 3 6 0 2014 1 3 6 0 2014 3 4 6 0 2015 1 1 0 0 ppublish 69740 10.1172/JCI69740 24382385 PMC3871233 24375250 2014 05 05 2014 06 24

1423-0380 35 5 2014 May Tumour Biol. Methylation of miR-124a-1, miR-124a-2, and miR-124a-3 genes correlates with aggressive and advanced breast cancer disease. 4047-56 10.1007/s13277-013-1530-4 Aberrant DNA methylation on CpG islands is one of the most consistent epigenetic changes in human cancers, and the process of methylation is catalyzed by the DNA methyltransferases DNMT1, DNMT3a, and DNMT3b. Recent reports demonstrate that deregulation of miR-124a, one of the frequently methylated microRNAs in human cancers, is related to carcinogenesis. The aim of this study was to evaluate the frequencies of methylation of the three genomic loci encoding the miR-124a in primary breast cancers and to investigate their relationships with the clinicopathological characteristics of the tumors and with the expression levels of DNMT1, DNMT3a, and DNMT3b. The methylation status of the three genomic loci encoding the miR-124a (miR-124a-1, miR-124a-2, and miR-124a-3) was analyzed in fresh-frozen tumor samples using methylation-specific PCR in a large series of invasive breast ductal carcinomas (n = 60). Results were correlated to several clinicopathological characteristics of the tumors and to the expression levels of DNMT1, DNMT3a, and DNMT3b, determined by immunohistochemistry. Promoter hypermethylation of miR-124a-1, miR-124a-2, and miR-124a-3 was detected in 53.3, 70, and 36.7% of cases, respectively. Methylation of miR-124a-2 correlated to patients with age higher than 45 years (P = 0.008) and to postmenopausal patients (P = 0.03), whereas methylation of miR-124a-3 correlated significantly to tumor size >20 mm (P = 0.03). Interestingly, simultaneous methylation of the three genes encoding miR-124a correlated significantly with the presence of lymph node metastasis (P = 0.01) and high mitotic score (P = 0.03). No significant correlation was found between promoter hypermethylation of miR-124a and expression of hormone receptors or HER2/neu. With regard to DNMT expression, no correlation was found between DNMT1 or DNMT3a expression and promoter methylation of any tested microRNA. However, DNMT3b overexpression correlates significantly with the hypermethylation of miR-124a-3 (P = 0.03). Our data indicates that miR-124a-1, miR-124a-2, and miR-124a-3 genes are frequently methylated in breast cancer and play a role in tumor growth and aggressivity. Ben Gacem Riadh R Department of Pathology, Farhat-Hached Hospital, Sousse, 4000, Tunisia. Ben Abdelkrim Olfa O Ziadi Sonia S Ben Dhiab Myriam M Trimeche Mounir M eng Journal Article Research Support, Non-U.S. Gov't 2013 12 29

Netherlands Tumour Biol 8409922 1010-4283 0 MIRN124 microRNA, human 0 MicroRNAs EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 EC 2.1.1.37 DNA methyltransferase 3A EC 2.1.1.37 DNA methyltransferase 3B IM Adult Aged Breast Neoplasms genetics pathology DNA (Cytosine-5-)-Methyltransferase analysis genetics DNA Methylation Disease Progression Female Humans MicroRNAs genetics Middle Aged Neoplasm Staging Promoter Regions, Genetic 2013 8 29 2013 12 11 2013 12 29 2013 12 31 6 0 2014 1 1 6 0 2014 6 25 6 0 ppublish 10.1007/s13277-013-1530-4 24375250 24362548 2014 09 13

1559-0267 47 2 2014 Oct Clin Rev Allergy Immunol Epigenetic alterations and microRNA misexpression in cancer and autoimmune diseases: a critical review. 128-35 10.1007/s12016-013-8401-z Epigenetic markers such as DNA methylation and histone modifications around promoter regions modify chromatin structure and regulate expression of downstream genes. In fact, aberrant epigenetic modifications are common events in human disease including tumorigenesis and autoimmunity. Small non-coding RNAs named microRNAs (miRNAs) are modulators of gene expression and play critical roles in various cellular processes. Several miRNAs have been characterized as tumor suppressors or oncogenes in cancer, and recent reports implicate certain miRNAs in the pathogenesis of autoimmune diseases. Epigenetic investigations have shown that distinct miRNAs are directly regulated by DNA methylation and histone modifications at their promoters. Moreover, miRNAs themselves are key participants in regulating the chromatin modifying machinery. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have shown efficacy in human malignancies and there is some evidence that these drugs may be useful in autoimmune disease. The benefits of these drugs are at least partially mediated by restoring expression of epigenetically silenced tumor suppressor genes, including miRNAs. The complex layers regulating gene expression have yet to be fully elucidated, but it is clear that epigenetic alterations and miRNA misexpression are essential events in pathologic processes, especially cancer and autoimmune disease, and represent promising therapeutic targets. Saito Yoshimasa Y Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan, yoshimasa.saito@gmail.com. Saito Hidetsugu H Liang Gangning G Friedman Jeffrey M JM eng R01 CA138794 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

United States Clin Rev Allergy Immunol 9504368 1080-0549 IM 2013 12 24 6 0 2013 12 24 6 0 2013 12 24 6 0 ppublish 10.1007/s12016-013-8401-z 24362548 24348521 2013 12 18 2014 06 24 2014 06 24

1664-8021 4 2013 Front Genet Disruption of the expression and function of microRNAs in lung cancer as a result of epigenetic changes. 275 10.3389/fgene.2013.00275 Two decades have passed since the discovery of microRNA (miRNA), which determines cell fate in nematodes. About one decade ago, the conservation of miRNA in humans was also discovered. At present, the loss of certain miRNAs and the overexpression of miRNAs have been demonstrated in many types of diseases, especially cancer. A key miRNA in lung cancer was reported soon after the initial discovery of a tumor-suppressive miRNA in a hematological malignancy. Various causes of miRNA disruption are known, including deletions, mutations, and epigenetic suppression as well as coding genes. The recent accumulation of knowledge regarding epigenetic transcriptional suppression has revealed the suppression of several miRNAs in lung cancer in response to epigenetic changes, such as H3K9 methylation prior to DNA methylation and H3K27 methylation independent of DNA methylation. In this review, recent knowledge of miRNA disruption in lung cancer as a result of epigenetic changes is discussed. Additionally, emerging cancer-specific changes in RNA editing and their impact on miRNA function are described. Watanabe Kousuke K Department of Respiratory Medicine, The University of Tokyo Hospital Bunkyo-ku, Tokyo, Japan. Takai Daiya D Department of Clinical Laboratory, The University of Tokyo Hospital Bunkyo-ku, Tokyo, Japan. eng Journal Article Review 2013 12 03

Switzerland Front Genet 101560621 1664-8021 PMC3847897 DNA methylation RNA editing histone modification lung cancer microRNA 2013 2013 9 18 2013 11 19 2013 12 03 2013 12 19 6 0 2013 12 19 6 0 2013 12 19 6 1 epublish 10.3389/fgene.2013.00275 24348521 PMC3847897 24348513 2013 12 18 2014 06 24 2014 06 24

1664-8021 4 2013 Front Genet Epigenetic alteration and microRNA dysregulation in cancer. 258 10.3389/fgene.2013.00258 MicroRNAs (miRNAs) play pivotal roles in numerous biological processes, and their dysregulation is a common feature of human cancer. Thanks to recent advances in the analysis of the cancer epigenome, we now know that epigenetic alterations, including aberrant DNA methylation and histone modifications, are major causes of miRNA dysregulation in cancer. Moreover, the list of miRNA genes silenced in association with CpG island hypermethylation is rapidly growing, and various oncogenic miRNAs are now known to be upregulated via DNA hypomethylation. Histone modifications also play important roles in the dysregulation of miRNAs, and histone deacetylation and gain of repressive histone marks are strongly associated with miRNA gene silencing. Conversely, miRNA dysregulation is causally related to epigenetic alterations in cancer. Thus aberrant methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Given that many of the silenced miRNAs appear to act as tumor suppressors through the targeting of oncogenes, re-expression of the miRNAs could be an effective approach to cancer therapy, and unraveling the relationship between epigenetic alteration and miRNA dysregulation may lead to the discovery of new therapeutic targets. Suzuki Hiromu H Department of Molecular Biology, Sapporo Medical University Sapporo, Japan. Maruyama Reo R Department of Molecular Biology, Sapporo Medical University Sapporo, Japan. Yamamoto Eiichiro E Department of Molecular Biology, Sapporo Medical University Sapporo, Japan. Kai Masahiro M Department of Molecular Biology, Sapporo Medical University Sapporo, Japan. eng Journal Article Review 2013 12 03

Switzerland Front Genet 101560621 1664-8021 PMC3847369 CpG island methylation EZH2 biomarker histone modification microRNA oncomir tumor suppressor 2013 2013 10 01 2013 11 11 2013 12 03 2013 12 19 6 0 2013 12 19 6 0 2013 12 19 6 1 epublish 10.3389/fgene.2013.00258 24348513 PMC3847369 24326628 2014 02 10

1538-7755 23 2 2014 Feb Cancer Epidemiol. Biomarkers Prev. Epigenetic research in cancer epidemiology: trends, opportunities, and challenges. 223-33 10.1158/1055-9965.EPI-13-0573 Epigenetics is emerging as an important field in cancer epidemiology that promises to provide insights into gene regulation and facilitate cancer control throughout the cancer care continuum. Increasingly, investigators are incorporating epigenetic analysis into the studies of etiology and outcomes. To understand current progress and trends in the inclusion of epigenetics in cancer epidemiology, we evaluated the published literature and the National Cancer Institute (NCI)-supported research grant awards in this field to identify trends in epigenetics research. We present a summary of the epidemiologic studies in NCI's grant portfolio (from January 2005 through December 2012) and in the scientific literature published during the same period, irrespective of support from the NCI. Blood cells and tumor tissue were the most commonly used biospecimens in these studies, although buccal cells, cervical cells, sputum, and stool samples were also used. DNA methylation profiling was the focus of the majority of studies, but several studies also measured microRNA profiles. We illustrate here the current status of epidemiologic studies that are evaluating epigenetic changes in large populations. The incorporation of epigenomic assessments in cancer epidemiology studies has and is likely to continue to provide important insights into the field of cancer research. Verma Mukesh M Authors' Affiliations: Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences; Division of Cancer Prevention, National Cancer Institute; Office of the Director, Information Resources and Services Branch, NIH, Bethesda, Maryland; and Office of Public Health Genomics, Centers for Disease Control and Prevention, Atlanta, Georgia. Rogers Scott S Divi Rao L RL Schully Sheri D SD Nelson Stefanie S Joseph Su L L Ross Sharon A SA Pilch Susan S Winn Deborah M DM Khoury Muin J MJ eng Journal Article 2013 12 10

United States Cancer Epidemiol Biomarkers Prev 9200608 1055-9965 IM NIHMS547865 [Available on 02/01/15] PMC3925982 [Available on 02/01/15] 2013 12 10 2014 1 22 2013 12 12 6 0 2013 12 12 6 0 2013 12 12 6 0 2015 2 1 0 0 ppublish 1055-9965.EPI-13-0573 10.1158/1055-9965.EPI-13-0573 24326628 PMC3925982 NIHMS547865 24295492 2014 01 06 2014 08 26

1875-5666 14 1 2014 Jan Curr. Mol. Med. DNA methylation and miRNAs regulation in hereditary breast cancer: epigenetic changes, players in transcriptional and post- transcriptional regulation in hereditary breast cancer. 45-57 The genetic alterations associated with breast carcinogenesis are well known. On the contrary epigenetic alterations in hereditary breast cancer are a new field. Two epigenetic mechanisms have emerged as the most critical players in transcriptional regulation in breast cancer: the methylation of DNA and microRNA interference. In this review we will focus on recent findings on gene silencing caused by DNA methylation and microRNA to explore the potential role of these epigenetic changes in the understanding of hereditary breast cancer. Moreover we will describe the same alterations in basal-like breast cancer and in triple-negative breast cancer, since their phenotypes have similarities with BRCA1-mutated tumors. To underline the possibility that some epigenetic alterations could also be used as potential epigenetic biomarkers of drug sensitivity or resistance, we will discuss the more common therapies in hereditary breast cancer that could also be applied to breast cancer with basal-like or triple negative phenotypes. Pinto R R De Summa S S Pilato B B Tommasi S S Molecular Genetics IRCCS "Giovanni Paolo II", v.le Orazio Flacco 65, 70124 Bari, Italy. s.tommasi@oncologico.bari.it. eng Journal Article Review

Netherlands Curr Mol Med 101093076 1566-5240 0 MicroRNAs 0 Tumor Markers, Biological Breast Cancer, Familial IM Breast Neoplasms congenital genetics metabolism therapy DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics metabolism Neoplasms, Basal Cell genetics metabolism RNA Processing, Post-Transcriptional Transcription, Genetic Triple Negative Breast Neoplasms genetics metabolism Tumor Markers, Biological 2013 1 12 2013 2 27 2013 6 04 2013 12 4 6 0 2013 12 4 6 0 2014 8 27 6 0 ppublish CMM-EPUB-57817 24295492 24219277 2013 11 13 2014 06 06

1208-6002 91 6 2013 Dec Biochem. Cell Biol. The epigenetic potentials of dietary polyphenols in prostate cancer management. 361-8 10.1139/bcb-2012-0044 Prostate cancer is a disease that is greatly affected by lifestyle, particularly diet, and is more prevalent in US and European countries compared with South and East Asia. Among several known causes and risk factors, nutrition plays an important role in prostate cancer pathogenesis. Various dietary components including polyphenols have been shown to possess anticancer properties. Dietary polyphenols have been the subject of extensive studies for the last decade because of their anticancer and chemopreventive potentials. Besides possessing various antitumor properties, dietary polyphenols also contribute to epigenetic changes associated with the fate of cancer cells and have emerged as potential drugs for therapeutic intervention. Various polyphenols have been shown to affect DNA methylation, histone posttranslational modifications, and microRNA expression patterns in prostate cancer. In this review, we discuss the contribution of dietary polyphenols to various epigenetic modifications in prostate cancer. Since prostate cancer and diet are intimately associated, polyphenol-rich diets that epigenetically modify tumor biology have great significance in the prevention and management of prostate cancer. Abbas Ata A Byrd Biotechnology Building, Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington WV 25755, USA. Patterson William W 3rd Georgel Philippe T PT eng 5P20RR-020180 RR NCRR NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review 2012 10 23

Canada Biochem Cell Biol 8606068 0829-8211 0 Histones 0 MicroRNAs 0 Polyphenols IM DNA Methylation Diet Epigenesis, Genetic Gene Expression Regulation, Neoplastic Histones genetics metabolism Humans Male MicroRNAs genetics metabolism Polyphenols administration & dosage Prostate drug effects metabolism pathology Prostatic Neoplasms genetics metabolism prevention & control Protein Processing, Post-Translational 2012 10 23 2013 11 14 6 0 2013 11 14 6 0 2014 6 7 6 0 ppublish 10.1139/bcb-2012-0044 24219277 24204564 2013 11 08 2014 08 04

1932-6203 8 10 2013 PLoS ONE Methylated DNA binding domain protein 2 (MBD2) coordinately silences gene expression through activation of the microRNA hsa-mir-496 promoter in breast cancer cell line. e74009 10.1371/journal.pone.0074009 Methylated DNA binding protein 2 (MBD2) binds methylated promoters and suppresses transcription in cis through recruitment of a chromatin modification repressor complex. We show here a new mechanism of action for MBD2: suppression of gene expression indirectly through activation of microRNA hsa-mir-496. Overexpression of MBD2 in breast epithelial cell line MCF-10A results in induced expression and demethylation of hsa-mir-496 while depletion of MBD2 in a human breast cancer cell lines MCF-7 and MDA-MB231 results in suppression of hsa-mir-496. Activation of hsa-mir-496 by MBD2 is associated with silencing of several of its target genes while depletion of MBD2 leads to induction of hsa-mir-496 target genes. Depletion of hsa-mir-496 by locked nucleic acid (LNA) antisense oligonucleotide leads to activation of these target genes in MBD2 overexpressing cells supporting that hsa-mir-496 is mediating in part the effects of MBD2 on gene expression. We demonstrate that MBD2 binds the promoter of hsa-mir-496 in MCF-10A, MCF-7 and MDA-MB-231 cells and that it activates an in vitro methylated hsa-mir-496 promoter driving a CG-less luciferase reporter in a transient transfection assay. The activation of hsa-mir-496 is associated with reduced methylation of the promoter. Taken together these results describe a novel cascade for gene regulation by DNA methylation whereby activation of a methylated microRNA by MBD2 that is associated with loss of methylation triggers repression of downstream targets. Alvarado Sebastian S Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada. Wyglinski Joanne J Suderman Matthew M Andrews Stephen A SA Szyf Moshe M eng MOP-42411 Canadian Institutes of Health Research Canada Journal Article Research Support, Non-U.S. Gov't 2013 10 29

United States PLoS One 101285081 1932-6203 0 DNA-Binding Proteins 0 MBD2 protein 0 MIRN496 microRNA, human 0 MicroRNAs IM Nat Genet. 1999 Sep;23(1):58-61 10471499 Nucleic Acids Res. 1994 Aug 11;22(15):2990-7 8065911 PLoS Biol. 2005 Mar;3(3):e85 15723116 Nature. 2005 Jun 9;435(7043):839-43 15944709 Nucleic Acids Res. 2006;34(1):364-72 16410616 Nat Genet. 2006 Feb;38(2):149-53 16444255 Nat Genet. 1997 Jul;16(3):256-9 9207790 Adv Exp Med Biol. 1997;421:253-7 9330705 Mol Cell Biol. 1998 Nov;18(11):6538-47 9774669 Oncogene. 1998 Nov 19;17(20):2573-83 9840920 Nature. 1999 Feb 18;397(6720):579-83 10050851 Mol Cell Biol. 1999 Apr;19(4):3198-204 10082586 Genes Dev. 1999 Aug 1;13(15):1924-35 10444591 Oncogene. 2006 Aug 31;25(39):5436-45 16607278 Cancer Res. 2006 Sep 15;66(18):9202-10 16982764 Cell Cycle. 2006 Oct;5(19):2220-2 17012846 Nat Genet. 2007 Apr;39(4):457-66 17334365 Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R50-9 17613547 Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15805-10 17890317 Epigenetics. 2006 Jul-Sep;1(3):127-30 17965610 Cancer Biol Ther. 2007 Aug;6(8):1284-8 17660710 J Pathol. 2008 Jan;214(1):17-24 17948228 Genes Dev. 2008 Nov 15;22(22):3172-83 19056895 Hum Reprod. 2009 Mar;24(3):562-79 19091803 J Immunol. 2009 Jun 15;182(12):7698-707 19494294 PLoS One. 2010;5(5):e10724 20505758 Mol Cancer Res. 2010 Jun;8(6):821-32 20530583 Exp Hematol. 2011 Mar;39(3):272-81 21168469 Cancer Res. 2011 Sep 1;71(17):5891-903 21747116 J Biol Chem. 2012 Jan 2;287(1):465-73 22074923 Oncogene. 2012 Apr 19;31(16):2062-74 21874049 Gastroenterology. 2012 Sep;143(3):811-20.e1-15 22641068 J Biol Chem. 2012 Sep 28;287(40):33116-21 22898819 J Biol Chem. 2013 Mar 29;288(13):9084-91 23393137 Cancer Biochem Biophys. 1999 Jul;17(1-2):69-78 10738903 Oncogene. 2002 Apr 18;21(17):2704-12 11965543 J Gene Med. 2002 Jul-Aug;4(4):381-9 12124980 Clin Cancer Res. 2004 May 1;10(9):3035-41 15131040 Carcinogenesis. 2004 Apr;25(4):499-507 14688029 J Biol Chem. 2002 Sep 27;277(39):35791-4 12177048 Nat Rev Genet. 2004 Jul;5(7):522-31 15211354 J Biol Chem. 2004 Jul 23;279(30):31735-44 15150277 EMBO J. 2004 Oct 13;23(20):4051-60 15372072 J Biol Chem. 2003 Apr 25;278(17):15333-40 12566445 Nat Genet. 2003 Jun;34(2):145-7 12730693 J Virol. 2003 Aug;77(16):8957-61 12885912 Cell. 2004 Jan 23;116(2):281-97 14744438 Science. 1980 Nov 7;210(4470):604-10 6254144 J Biol Chem. 1992 Apr 15;267(11):7368-77 1559980 Genomics. 1992 Jun;13(2):395-401 1612598 Oncogene. 2005 Mar 10;24(11):1914-23 15674330 Breast Neoplasms genetics metabolism Cell Line, Tumor DNA Methylation DNA-Binding Proteins genetics metabolism Female Gene Expression Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Regulatory Networks Gene Silencing Genes, Reporter Humans MCF-7 Cells MicroRNAs genetics Promoter Regions, Genetic Transcriptional Activation PMC3812180 2013 2013 4 11 2013 7 25 2013 10 29 2013 11 9 6 0 2013 11 10 6 0 2014 8 5 6 0 epublish 10.1371/journal.pone.0074009 PONE-D-13-15017 24204564 PMC3812180 24202331 2013 11 08 2013 11 08 2013 11 12

2072-6694 5 3 2013 Cancers (Basel) The Interactions of microRNA and Epigenetic Modifications in Prostate Cancer. 998-1019 10.3390/cancers5030998 Epigenetic modifiers play important roles in fine-tuning the cellular transcriptome. Any imbalance in these processes may lead to abnormal transcriptional activity and thus result in disease state. Distortions of the epigenome have been reported in cancer initiation and progression. DNA methylation and histone modifications are principle components of this epigenome, but more recently it has become clear that microRNAs (miRNAs) are another major component of the epigenome. Interactions of these components are apparent in prostate cancer (CaP), which is the most common non-cutaneous cancer and second leading cause of death from cancer in the USA. Changes in DNA methylation, altered histone modifications and miRNA expression are functionally associated with CaP initiation and progression. Various aspects of the epigenome have also been investigated as biomarkers for different stages of CaP detection, though with limited success. This review aims to summarize key aspects of these mechanistic interactions within the epigenome and to highlight their translational potential as functional biomarkers. To this end, exploration of TCGA prostate cancer data revealed that expression of key CaP miRNAs inversely associate with DNA methylation. Given the importance and prevalence of these epigenetic events in CaP biology it is timely to understand further how different epigenetic components interact and influence each other. Singh Prashant Kumar PK Department of Pharmacology & Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. Prashant.singh@roswellpark.org. Campbell Moray J MJ eng Journal Article 2013 08 09

Switzerland Cancers (Basel) 101526829 2072-6694 PMC3795376 2013 6 26 2013 7 16 2013 7 24 2013 11 9 6 0 2013 11 10 6 0 2013 11 10 6 1 epublish cancers5030998 10.3390/cancers5030998 24202331 PMC3795376 24173286 2013 11 26 2014 09 05

1791-2431 31 1 2014 Jan Oncol. Rep. Androgen receptor is negatively correlated with the methylation-mediated transcriptional repression of miR-375 in human prostate cancer cells. 34-40 10.3892/or.2013.2810 Androgen receptor (AR) plays a critical role during the development and progression of prostate cancer in which microRNA miR-375 is overexpressed and correlated with tumor progression. Although DNA methylation is a key mechanism for the repression of gene expression, the relationship between AR and the expression or the hypermethylation of miR-375 is unknown. In this study, we found that AR-positive prostate cancer (PCa) cells showed high expression levels and hypomethylation of the miR-375. In contrast, AR-negative PCa cells displayed low levels and hypermethylation of the miR-375. Addition of 5-Aza-2'-deoxycytidine, a specific inhibitor of DNA methylation, into the culture medium reversed the low expression levels of miR-375 in the AR negative PCa cells. In addition, the total activity levels of DNA methyltransferases (DNMTs) were high in AR-negative PCa cells, in which hypermethylation of miR-375 promoter and low expression levels of miR-375 were observed. Taken together, these findings indicate that the negative correlation between AR and total DNMT activity is one of mechanisms to influence the methylation status of miR-375 promoter, which in turn regulates the expression of miR-375. Chu Mingliang M State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China. Chang Yunli Y Li Ping P Guo Yanjing Y Zhang Kaiqing K Gao Weiqiang W eng Journal Article Research Support, Non-U.S. Gov't 2013 10 24

Greece Oncol Rep 9422756 1021-335X 0 AR protein, human 0 Antimetabolites, Antineoplastic 0 Enzyme Inhibitors 0 MIRN375 microRNA, human 0 MicroRNAs 0 RNA, Small Interfering 0 Receptors, Androgen 776B62CQ27 decitabine EC 2.1.1.- DNA Modification Methylases M801H13NRU Azacitidine IM Cell. 1999 Oct 29;99(3):247-57 10555141 Mol Cancer Res. 2011 Jun;9(6):791-800 21593139 Am J Pathol. 2011 Nov;179(5):2580-8 21945323 J Hum Genet. 2011 Aug;56(8):595-601 21753766 FEBS Lett. 2011 Aug 4;585(15):2467-76 21723283 Int J Biol Sci. 2011;7(6):815-22 21750650 Br J Cancer. 2011 Jun 28;105(1):104-11 21673684 Cancer Res. 2009 Sep 15;69(18):7412-21 19723660 RNA. 2009 Aug;15(8):1443-61 19561119 Mol Nutr Food Res. 2009 Feb;53(2):171-84 19101947 Nat Rev Genet. 2007 Feb;8(2):93-103 17230196 Biol Chem. 2006 Jun;387(6):707-14 16800731 Cancer Res. 1999 Sep 1;59(17):4180-4 10485450 Cancer Res. 1998 Dec 15;58(24):5718-24 9865729 Steroids. 1996 Sep;61(9):531-9 8883219 Endocr Rev. 2004 Apr;25(2):276-308 15082523 Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004 14973191 Epidemiol Rev. 2000;22(2):239-48 11218375 Proc Natl Acad Sci U S A. 2011 May 31;108(22):9055-9 21518897 Br J Cancer. 2011 Mar 1;104(5):830-40 21326242 Cancer Res. 2010 Nov 15;70(22):9175-84 20978187 Biochem Biophys Res Commun. 2010 Apr 9;394(3):623-7 20226166 Oncogene. 2014 Jan 9;33(2):135-47 23455326 Oncogene. 2013 Jan 3;32(1):127-34 22310291 Cancer Res. 2003 Aug 1;63(15):4299-304 12907594 Bioinformatics. 2002 Nov;18(11):1427-31 12424112 Oncogene. 2002 Aug 1;21(33):5069-80 12140757 Gynecol Oncol. 2001 Aug;82(2):299-304 11531283 Mol Carcinog. 2002 Mar;33(3):163-71 11870882 J Biol Chem. 2002 May 3;277(18):16048-58 11844796 Antimetabolites, Antineoplastic pharmacology Azacitidine analogs & derivatives pharmacology Cell Line, Tumor DNA Methylation genetics DNA Modification Methylases biosynthesis Enzyme Inhibitors pharmacology Gene Expression Gene Expression Regulation, Neoplastic genetics Humans Male MicroRNAs biosynthesis genetics Promoter Regions, Genetic genetics Prostatic Neoplasms genetics RNA Interference RNA, Small Interfering Receptors, Androgen genetics Transcriptional Activation genetics PMC3868498 2013 9 11 2013 10 13 2013 10 24 2013 11 1 6 0 2013 11 1 6 0 2014 9 6 6 0 ppublish 10.3892/or.2013.2810 24173286 PMC3868498 24163742 2013 10 28 2014 06 24 2014 08 20

2072-1439 5 Suppl 5 2013 Oct J Thorac Dis An emerging place for lung cancer genomics in 2013. S491-7 10.3978/j.issn.2072-1439.2013.10.06 Lung cancer is a disease with a dismal prognosis and is the biggest cause of cancer deaths in many countries. Nonetheless, rapid technological developments in genome science promise more effective prevention and treatment strategies. Since the Human Genome Project, scientific advances have revolutionized the diagnosis and treatment of human cancers, including thoracic cancers. The latest, massively parallel, next generation sequencing (NGS) technologies offer much greater sequencing capacity than traditional, capillary-based Sanger sequencing. These modern but costly technologies have been applied to whole genome-, and whole exome sequencing (WGS and WES) for the discovery of mutations and polymorphisms, transcriptome sequencing for quantification of gene expression, small ribonucleic acid (RNA) sequencing for microRNA profiling, large scale analysis of deoxyribonucleic acid (DNA) methylation and chromatin immunoprecipitation mapping of DNA-protein interaction. With the rise of personalized cancer care, based on the premise of precision medicine, sequencing technologies are constantly changing. To date, the genomic landscape of lung cancer has been captured in several WGS projects. Such work has not only contributed to our understanding of cancer biology, but has also provided impetus for technical advances that may improve our ability to accurately capture the cancer genome. Issues such as short read lengths contribute to sequenced libraries that contain challenging gaps in the aligned genome. Emerging platforms promise longer reads as well as the ability to capture a range of epigenomic signals. In addition, ongoing optimization of bioinformatics strategies for data analysis and interpretation are critical, especially for the differentiation between driver and passenger mutations. Moreover, broader deployment of these and future generations of platforms, coupled with an increasing bioinformatics workforce with access to highly sophisticated technologies, could see many of these discoveries translated to the clinic at a rapid pace. We look forward to these advances making a difference for the many patients we treat in the Asia-Pacific region and around the world. Daniels Marissa G MG The University of Queensland and the Prince Charles Hospital Thoracic Research Centre, the Prince Charles Hospital, Chermside 4032, Australia; Bowman Rayleen V RV Yang Ian A IA Govindan Ramaswamy R Fong Kwun M KM eng Journal Article Review

China J Thorac Dis 101533916 2072-1439 PMC3804884 High-throughput nucleotide sequencing genomics lung neoplasms non-small cell lung carcinoma (NSCLC) small cell lung carcinoma (SCLC) 2013 10 10 2013 10 12 2013 10 29 6 0 2013 10 29 6 0 2013 10 29 6 1 ppublish 10.3978/j.issn.2072-1439.2013.10.06 jtd-05-S5-S491 24163742 PMC3804884 24152442 2013 10 24 2014 04 24

1422-0067 14 10 2013 Int J Mol Sci Cancer development, progression, and therapy: an epigenetic overview. 21087-113 10.3390/ijms141021087 Carcinogenesis involves uncontrolled cell growth, which follows the activation of oncogenes and/or the deactivation of tumor suppression genes. Metastasis requires down-regulation of cell adhesion receptors necessary for tissue-specific, cell-cell attachment, as well as up-regulation of receptors that enhance cell motility. Epigenetic changes, including histone modifications, DNA methylation, and DNA hydroxymethylation, can modify these characteristics. Targets for these epigenetic changes include signaling pathways that regulate apoptosis and autophagy, as well as microRNA. We propose that predisposed normal cells convert to cancer progenitor cells that, after growing, undergo an epithelial-mesenchymal transition. This process, which is partially under epigenetic control, can create a metastatic form of both progenitor and full-fledged cancer cells, after which metastasis to a distant location may occur. Identification of epigenetic regulatory mechanisms has provided potential therapeutic avenues. In particular, epigenetic drugs appear to potentiate the action of traditional therapeutics, often by demethylating and re-expressing tumor suppressor genes to inhibit tumorigenesis. Epigenetic drugs may inhibit both the formation and growth of cancer progenitor cells, thus reducing the recurrence of cancer. Adopting epigenetic alteration as a new hallmark of cancer is a logical and necessary step that will further encourage the development of novel epigenetic biomarkers and therapeutics. Sarkar Sibaji S Cancer Center, L913, Department of Medicine, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. ss1@bu.edu. Horn Garrick G Moulton Kimberly K Oza Anuja A Byler Shannon S Kokolus Shannon S Longacre McKenna M eng Journal Article Research Support, Non-U.S. Gov't Review 2013 10 21

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14;150(6):1135-46 22980977 Cell Mol Life Sci. 2012 Oct;69(20):3429-56 22945800 Cell Death Differ. 2012 Nov;19(11):1750-60 22555458 Nat Struct Mol Biol. 2012 Nov;19(11):1155-60 23022729 Mol Biol Rep. 2013 Jan;40(1):309-25 23086271 Pharmacol Ther. 2013 Feb;137(2):153-71 23041058 Animals Carcinogenesis genetics pathology Disease Progression Epigenesis, Genetic genetics Humans Neoplasms genetics pathology therapy PMC3821660 2013 8 30 2013 9 27 2013 10 04 2013 10 25 6 0 2013 10 25 6 0 2014 4 25 6 0 epublish ijms141021087 10.3390/ijms141021087 24152442 PMC3821660 24130964 2013 10 16 2014 06 24 2014 06 24

2234-943X 3 2013 Front Oncol Targeting the epigenome in lung cancer: expanding approaches to epigenetic therapy. 261 10.3389/fonc.2013.00261 Epigenetic aberrations offer dynamic and reversible targets for cancer therapy; increasingly, alteration via overexpression, mutation, or rearrangement is found in genes that control the epigenome. Such alterations suggest a fundamental role in carcinogenesis. Here, we consider three epigenetic mechanisms: DNA methylation, histone tail modification and non-coding, microRNA regulation. Evidence for each of these in lung cancer origin or progression has been gathered, along with evidence that epigenetic alterations might be useful in early detection. DNA hypermethylation of tumor suppressor promoters has been observed, along with global hypomethylation and hypoacetylation, suggesting an important role for tumor suppressor gene silencing. These features have been linked as prognostic markers with poor outcome in lung cancer. Several lines of evidence have also suggested a role for miRNA in carcinogenesis and in outcome. Cigarette smoke downregulates miR-487b, which targets both RAS and MYC; RAS is also a target of miR-let-7, again downregulated in lung cancer. Together the evidence implicates epigenetic aberration in lung cancer and suggests that targeting these aberrations should be carefully explored. To date, DNA methyltransferase and histone deacetylase inhibitors have had minimal clinical activity. Explanations include the possibility that the agents are not sufficiently potent to invoke epigenetic reversion to a more normal state; that insufficient time elapses in most clinical trials to observe true epigenetic reversion; and that doses often used may provoke off-target effects such as DNA damage that prevent epigenetic reversion. Combinations of epigenetic therapies may address those problems. When epigenetic agents are used in combination with chemotherapy or targeted therapy it is hoped that downstream biological effects will provoke synergistic cytotoxicity. This review evaluates the challenges of exploiting the epigenome in the treatment of lung cancer. Jakopovic Marko M University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb , Zagreb , Croatia. Thomas Anish A Balasubramaniam Sanjeeve S Schrump David D Giaccone Giuseppe G Bates Susan E SE eng Journal Article Review 2013 10 09

Switzerland Front Oncol 101568867 2234-943X PMC3793201 DNA methylation epigenetics histone modification microRNA non-small cell lung cancer small-cell lung cancer 2013 2013 7 15 2013 9 18 2013 10 09 2013 10 17 6 0 2013 10 17 6 0 2013 10 17 6 1 epublish 10.3389/fonc.2013.00261 24130964 PMC3793201 24113142 2013 10 30 2014 02 20 2014 10 30

1532-1827 109 9 2013 Oct 29 Br. J. Cancer A microRNA-based prediction algorithm for diagnosis of non-small lung cell carcinoma in minimal biopsy material. 2404-11 10.1038/bjc.2013.623 Diagnosis is jeopardised when limited biopsy material is available or histological quality compromised. Here we developed and validated a prediction algorithm based on microRNA (miRNA) expression that can assist clinical diagnosis of lung cancer in minimal biopsy material to improve clinical management. Discovery utilised Taqman Low Density Arrays (754 miRNAs) in 20 non-small cell lung cancer (NSCLC) tumour/normal pairs. In an independent set of 40 NSCLC patients, 28 miRNA targets were validated using qRT-PCR. A prediction algorithm based on eight miRNA targets was validated blindly in a third independent set of 47 NSCLC patients. The panel was also tested in formalin-fixed paraffin-embedded (FFPE) specimens from 20 NSCLC patients. The genomic methylation status of highly deregulated miRNAs was investigated by pyrosequencing. In the final, frozen validation set the panel had very high sensitivity (97.5%), specificity (96.3%) and ROC-AUC (0.99, P=10(-15)). The panel provided 100% sensitivity and 95% specificity in FFPE tissue (ROC-AUC=0.97 (P=10(-6))). DNA methylation abnormalities contribute little to the deregulation of the miRNAs tested. The developed prediction algorithm is a valuable potential biomarker for assisting lung cancer diagnosis in minimal biopsy material. A prospective validation is required to measure the enhancement of diagnostic accuracy of our current clinical practice. Bediaga N G NG 1] Roy Castle Lung Cancer Research programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK [2] BIOMICs Research Group, University of the Basque Country, Vitoria, Spain. Davies M P A MP Acha-Sagredo A A Hyde R R Raji O Y OY Page R R Walshaw M M Gosney J J Alfirevic A A Field J K JK Liloglou T T eng Journal Article Research Support, Non-U.S. Gov't 2013 10 10

England Br J Cancer 0370635 0007-0920 0 MicroRNAs 0 Tumor Markers, Biological IM Cancer Res. 2012 Aug 15;72(16):4037-46 22761336 Lung Cancer. 2012 Jul;77(1):16-23 22306127 Clin Cancer Res. 2012 Dec 1;18(23):6416-25 23045246 PLoS One. 2013;8(2):e56333 23418554 Int J Cancer. 2009 Jan 1;124(1):81-7 18823011 Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1814-9 19188590 BMC Bioinformatics. 2008;9:439 18925941 Cancer Res. 2009 Jul 1;69(13):5553-9 19549910 Annu Rev Med. 2009;60:167-79 19630570 Eur J Cancer. 2009 Aug;45(12):2197-206 19493678 J Pathol. 2011 Jan;223(2):102-15 21125669 Cancer Res. 2010 Dec 1;70(23):9570-80 21118966 PLoS One. 2010;5(12):e15797 21203424 Int J Cancer. 2010 Dec 15;127(12):2870-8 21351266 Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3713-8 21300873 Cancer Biol Ther. 2011 Mar 1;11(5):490-6 21383543 Br J Cancer. 2011 Sep 27;105(7):1049-53 21863024 BMC Cancer. 2011;11:393 21920043 PLoS One. 2011;6(10):e26502 22046296 Cancer Sci. 2011 Dec;102(12):2126-31 21917081 PLoS One. 2012;7(2):e32307 22389695 Lung Cancer. 2012 Apr;76(1):32-8 22047961 Methods. 2001 Dec;25(4):402-8 11846609 Cancer Sci. 2005 Feb;96(2):111-5 15723655 Br J Cancer. 2006 Feb 27;94(4):561-8 16449996 Cancer Cell. 2006 Mar;9(3):189-98 16530703 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Nature. 2007 Jun 28;447(7148):1130-4 17554337 RNA. 2007 Oct;13(10):1668-74 17698639 Trends Pharmacol Sci. 2008 Jan;29(1):12-5 18068232 FEBS Lett. 2008 Oct 29;582(25-26):3663-8 18840437 J Biol Chem. 2009 Aug 21;284(34):23094-106 19546220 Exp Lung Res. 2009 Oct;35(8):646-64 19895320 Carcinogenesis. 2009 Nov;30(11):1903-9 19736307 Bioinformatics. 2009 Dec 15;25(24):3325-6 19808880 Mech Ageing Dev. 2009 Nov-Dec;130(11-12):731-41 19782699 Clin Cancer Res. 2010 Feb 15;16(4):1119-28 20145172 Clin Chem. 2010 Jun;56(6):998-1006 20378769 Mod Pathol. 2010 Aug;23(8):1157-64 20526284 CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300 20610543 Mol Cancer Res. 2010 Sep;8(9):1207-16 20696752 BMC Cancer. 2010;10:502 20858276 Clin Cancer Res. 2012 Mar 15;18(6):1619-29 22282464 Int J Cancer. 2012 Jun 1;130(11):2580-90 21702040 Cancer Res. 2012 Nov 15;72(22):5692-701 22962272 Aged Algorithms Biopsy Carcinoma, Non-Small-Cell Lung diagnosis genetics pathology DNA Methylation Female Gene Expression Humans Lung Neoplasms diagnosis genetics pathology Male MicroRNAs genetics Models, Biological Models, Statistical Paraffin Embedding Tumor Markers, Biological genetics PMC3817343 2013 6 1 2013 9 12 2013 9 18 2013 10 10 2013 10 12 6 0 2013 10 12 6 0 2014 2 22 6 0 ppublish bjc2013623 10.1038/bjc.2013.623 24113142 PMC3817343 24091729 2013 12 06 2014 07 22

1551-4005 12 23 2013 Dec 1 Cell Cycle miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells. 3650-62 10.4161/cc.26585 Epigenetic silencing of tumor suppressor genes frequently occurs and may account for their inactivation in cancer cells. We previously demonstrated that miR-29b is a tumor suppressor microRNA (miRNA) that targets de novo DNA methyltransferases and reduces the global DNA methylation of multiple myeloma (MM) cells. Here, we provide evidence that epigenetic activity of miR-29b leads to promoter demethylation of suppressor of cytokine signaling-1 (SOCS-1), a hypermethylated tumor suppressor gene. Enforced expression of synthetic miR-29b mimics in MM cell lines resulted in SOCS-1 gene promoter demethylation, as assessed by Sequenom MassARRAY EpiTYPER analysis, and SOCS-1 protein upregulation. miR-29b-induced SOCS-1 demethylation was associated with reduced STAT3 phosphorylation and impaired NFκB activity. Downregulation of VEGF-A and IL-8 mRNAs could be detected in MM cells transfected with miR-29b mimics as well as in endothelial (HUVEC) or stromal (HS-5) cells treated with conditioned medium from miR-29b-transfected MM cells. Notably, enforced expression of miR-29b mimics increased adhesion of MM cells to HS-5 and reduced migration of both MM and HUVEC cells. These findings suggest that miR-29b is a negative regulator of either MM or endothelial cell migration. Finally, the proteasome inhibitor bortezomib, which induces the expression of miR-29b, decreased global DNA methylation by a miR-29b-dependent mechanism and induced SOCS-1 promoter demethylation and protein upregulation. In conclusion, our data indicate that miR-29b is endowed with epigenetic activity and mediates previously unknown functions of bortezomib in MM cells. Amodio Nicola N Department of Experimental and Clinical Medicine; Magna Graecia University and Medical Oncology Unit; T. Campanella Cancer Center; Salvatore Venuta University Campus; Catanzaro, Italy. Bellizzi Dina D Leotta Marzia M Raimondi Lavinia L Biamonte Lavinia L D'Aquila Patrizia P Di Martino Maria Teresa MT Calimeri Teresa T Rossi Marco M Lionetti Marta M Leone Emanuela E Passarino Giuseppe G Neri Antonino A Giordano Antonio A Tagliaferri Pierosandro P Tassone Pierfrancesco P eng Journal Article Research Support, Non-U.S. Gov't 2013 09 25

United States Cell Cycle 101137841 1551-4005 0 Interleukin-8 0 MIRN29 microRNA, human 0 MicroRNAs 0 NF-kappa B 0 SOCS1 protein, human 0 STAT3 Transcription Factor 0 STAT3 protein, human 0 Suppressor of Cytokine Signaling Proteins 0 Vascular Endothelial Growth Factor A IM Cell Cycle. 2013 Dec 15;12(24):3718-9 24189534 Cell Movement genetics DNA Methylation Gene Expression Regulation Gene Expression Regulation, Neoplastic Human Umbilical Vein Endothelial Cells Humans Interleukin-8 genetics metabolism MicroRNAs genetics metabolism Multiple Myeloma metabolism pathology NF-kappa B metabolism Phosphorylation Promoter Regions, Genetic STAT3 Transcription Factor metabolism Signal Transduction Suppressor of Cytokine Signaling Proteins genetics metabolism Tumor Cells, Cultured Vascular Endothelial Growth Factor A genetics metabolism PMC3903716 [Available on 12/01/14] epi-miRNA methylation miR-29b microRNA multiple myeloma 2013 9 25 2013 10 5 6 0 2013 10 5 6 0 2014 7 23 6 0 2014 12 1 0 0 ppublish 24091729 26585 10.4161/cc.26585 PMC3903716 24085423 2013 10 02 2014 06 11

1676-5680 12 3 2013 Genet. Mol. Res. Methylation regulation of liver-specific microRNA-122 expression and its effects on the proliferation and apoptosis of hepatocellular carcinoma cells. 3588-97 10.4238/2013.September.13.3 The regulation mechanism and significance of microRNA-122 (miRNA-122) expression are unclear. The aim of this study was to investigate the effects of DNA methylation on liver-specific miRNA-122 expression, cell proliferation, and apoptosis in hepatocellular carcinoma. Methylation of the miRNA-122 promoter region was detected through methylation sequencing. The level of miRNA-122 expression was measured using real-time quantitative polymerase chain reaction. The proliferation and apoptosis of hepatocellular cell lines were detected using flow cytometry and Cell Counting Kit-8 assays. Compared with those in human primary hepatocytes, methylation levels of the miRNA-122 promoter in the Huh7, HepG2, and QSG-7701 cell lines were significantly increased (P = 0.000). Similarly, levels of miRNA-122 expression in these cell lines significantly decreased (P = 0.007). After treatment with 5-aza-2-deoxycytidine, the Huh7 and HepG2 cell lines displayed a significantly lower degree of methylation (P = 0.038 and 0.025), and the levels of miRNA-122 expression were significantly higher (P = 0.008 and 0.003) than those in the blank group. Compared with the blank group, apoptosis of Huh7 and HepG2 cells was significantly increased (P = 0.001 and 0.027). We concluded that the expression of miRNA-122 is regulated by DNA methylation and correlated with apoptosis of liver cancer cells. Methylation regulation of miRNA-122 expression might be involved in the development of hepatocellular carcinoma. Xing T J TJ Department of Infectious Diseases, Taizhou People's Hospital, Taizhou, China xingtj518@sina.com. Xu H T HT Yu W Q WQ Jiang D F DF eng Journal Article 2013 09 13

Brazil Genet Mol Res 101169387 1676-5680 0 Antimetabolites, Antineoplastic 0 MIRN122 microRNA, human 0 MicroRNAs 776B62CQ27 decitabine M801H13NRU Azacitidine IM Antimetabolites, Antineoplastic pharmacology Apoptosis genetics Azacitidine analogs & derivatives pharmacology Carcinoma, Hepatocellular metabolism Cell Line, Tumor Cell Proliferation DNA Methylation Gene Expression Regulation, Neoplastic Hepatocytes metabolism Humans Liver cytology metabolism Liver Neoplasms metabolism MicroRNAs genetics metabolism Promoter Regions, Genetic 2013 10 3 6 0 2013 10 3 6 0 2014 6 12 6 0 epublish gmr2541 10.4238/2013.September.13.3 24085423 24046120 2013 12 24 2014 09 04

1534-4681 21 1 2014 Jan Ann. Surg. Oncol. Up-regulation of NEK2 by microRNA-128 methylation is associated with poor prognosis in colorectal cancer. 205-12 10.1245/s10434-013-3264-3 NIMA-related kinase 2 (NEK2), an enzyme involved in the development and progression of cancer, is abnormally expressed in a wide variety of human cancers, including colorectal cancer (CRC), and is known to have roles in cell division and mitotic regulation through centrosome splitting. We investigated the clinical significance of NEK2 in CRC. In particular, we examined miR-128 expression, which is thought to target NEK2. We measured NEK2 mRNA and miR-128 levels in clinical samples by quantitative reverse transcription real-time PCR and analyzed the associations between NEK2 levels, miR-128 levels, clinicopathological factors, and prognoses. Furthermore, we performed in vitro assays using a pre-miR-128 precursor and conducted miR-128 methylation analyses. MiR-128 inhibited NEK2 expression and cancer cell proliferation via cell cycle arrest. Moreover, miR-128 was silenced by DNA methylation. Increased NEK2 expression was associated with serosal invasion, lymphatic invasion, and peritoneal dissemination. Patients with high NEK2 expression also had significantly poorer prognoses. Multivariate analysis indicated that high NEK2 expression was an independent prognostic factor for survival. Patients with high miR-128 expression had significantly lower NEK2 expression and lower recurrence rates than those with low miR-128 expression. NEK2 may be an independent prognostic factor for CRC and was regulated by miR-128, a microRNA that was subjected to epigenetic regulation. Thus, this miR-128/NEK2 pathway may be a prospective therapeutic target for patients with CRC. Takahashi Yusuke Y Department of Surgery, Beppu Hospital, Kyushu University, Beppu, Japan. Iwaya Takeshi T Sawada Genta G Kurashige Junji J Matsumura Tae T Uchi Ryutaro R Ueo Hiroki H Takano Yuki Y Eguchi Hidetoshi H Sudo Tomoya T Sugimachi Keishi K Yamamoto Hirofumi H Doki Yuichiro Y Mori Masaki M Mimori Koshi K eng Journal Article Research Support, Non-U.S. Gov't 2013 09 18

United States Ann Surg Oncol 9420840 1068-9265 0 MIRN128 microRNA, human 0 MicroRNAs 0 RNA, Messenger 0 RNA, Small Interfering 0 Tumor Markers, Biological EC 2.7.1.- NEK2 protein, human EC 2.7.11.1 Protein-Serine-Threonine Kinases IM Aged Apoptosis Blotting, Western Cell Cycle Cell Proliferation Colorectal Neoplasms genetics mortality pathology DNA Methylation Female Follow-Up Studies Humans Liver Neoplasms genetics mortality secondary Lymphatic Metastasis Male MicroRNAs genetics Neoplasm Invasiveness Neoplasm Staging Peritoneal Neoplasms genetics mortality secondary Prognosis Protein-Serine-Threonine Kinases antagonists & inhibitors genetics metabolism RNA, Messenger genetics RNA, Small Interfering genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Survival Rate Tumor Cells, Cultured Tumor Markers, Biological genetics metabolism Up-Regulation 2013 6 10 2013 9 18 2013 9 19 6 0 2013 9 21 6 0 2014 9 5 6 0 ppublish 10.1245/s10434-013-3264-3 24046120 24045437 2013 09 18 2014 06 23

2045-2322 3 2013 Sci Rep Epigenetic silencing of microRNA-203 is required for EMT and cancer stem cell properties. 2687 10.1038/srep02687 The epithelial-mesenchymal transition (EMT) imparts metastatic competence on otherwise non-metastatic cancer cells through decreased inter-cellular adhesions, increased migratory capacity, stem cell properties and anoikis and chemotherapy resistance. In this study, we profiled changes in microRNA expression during EMT in conjunction with changes in DNA methylation at microRNA promoters to discover essential mediators of EMT-imparted stemness properties. MicroRNA-203 (miR-203) expression is repressed following EMT induced by multiple different stimuli and in established claudin-low cell lines as well as the CD44hi/CD24lo stem cell-enriched fraction. Expression of miR-203 in mesenchymal cells compromises migratory and invasive capacity in vitro, and tumor initiation and metastasis in vivo. Unexpectedly, miR-203 expression affects the sphere-forming capacity of neighboring cells by indirectly enhancing expression of DKK1, a secreted inhibitor of Wnt signaling and stemness resulting in suppression of β-catenin protein levels. Our data suggest that restoring miR-203 expression levels may inhibit metastasis and combat deregulated Wnt signaling. Taube Joseph H JH 1] Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA [2] Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA [3] Center for Stem Cells & Developmental Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA. Malouf Gabriel G GG Lu Emily E Sphyris Nathalie N Vijay Vidya V Ramachandran Priyanka P PP Ueno Katumasa R KR Gaur Sanchaika S Nicoloso Milena S MS Rossi Simona S Herschkowitz Jason I JI Rosen Jeffrey M JM Issa Jean-Pierre J JP Calin George A GA Chang Jeffrey T JT Mani Sendurai A SA eng CA16672 CA NCI NIH HHS United States R00LM009837 LM NLM NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

England Sci Rep 101563288 2045-2322 0 DKK1 protein, human 0 Intercellular Signaling Peptides and Proteins 0 MIRN203 microRNA, human 0 MicroRNAs 0 beta Catenin IM Nat Rev Cancer. 2013 Feb;13(2):97-110 23344542 Gene. 2013 Mar 15;517(1):72-81 23296057 Cell Death Dis. 2013;4:e514 23449450 Development. 2013 May;140(9):1882-91 23571213 Cancer Lett. 2000 Jan 1;148(1):73-80 10680595 Cancer Res. 2000 Aug 15;60(16):4346-8 10969774 Genes Dev. 2001 Jan 1;15(1):50-65 11156605 Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21 11309499 FEBS Lett. 2002 Jul 31;524(1-3):139-44 12135756 Nat Rev Cancer. 2002 Jun;2(6):442-54 12189386 Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3983-8 12629218 Genes Dev. 2003 May 15;17(10):1253-70 12756227 Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):266-71 14695885 Cell. 2004 Jun 25;117(7):927-39 15210113 Cancer Cell. 2004 Nov;6(5):497-506 15542433 Methods Enzymol. 2007;427:193-213 17720486 Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53 18158296 Nature. 2008 Mar 13;452(7184):225-9 18311128 Genes Dev. 2008 Apr 1;22(7):894-907 18381893 Nat Cell Biol. 2008 May;10(5):593-601 18376396 Cell. 2008 May 16;133(4):704-15 18485877 Dev Cell. 2008 Jun;14(6):818-29 18539112 PLoS One. 2008;3(8):e2888 18682804 Cancer Res. 2008 Oct 1;68(19):7846-54 18829540 Nat Genet. 2009 Mar;41(3):365-70 19219043 Nat Rev Cancer. 2009 Apr;9(4):265-73 19262571 Nat Rev Cancer. 2009 Apr;9(4):293-302 19262572 J Clin Invest. 2009 Jun;119(6):1420-8 19487818 J Immunol Methods. 2009 Aug 15;347(1-2):70-8 19567251 Cell. 2009 Aug 7;138(3):592-603 19665978 PLoS One. 2009;4(9):e7181 19787069 Nat Cell Biol. 2009 Dec;11(12):1487-95 19935649 PLoS One. 2010;5(1):e8697 20084174 PLoS One. 2010;5(6):e11014 20543981 Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54 20713713 Cancer Res. 2011 Apr 15;71(8):3087-97 21363915 Nat Struct Mol Biol. 2011 Aug;18(8):867-74 21725293 Mol Cell. 2011 Sep 2;43(5):811-22 21884981 Nat Med. 2011 Sep;17(9):1101-8 21822286 Nat Genet. 2012 Jan;44(1):23-31 22138693 Biol Cell. 2012 Jan;104(1):3-12 22188537 Trends Genet. 2012 Sep;28(9):454-63 22717049 J Exp Clin Cancer Res. 2012;31:58 22713668 Virchows Arch. 2012 Oct;461(4):441-8 22956368 Exp Cell Res. 2013 Jan 15;319(2):160-9 22935683 Cancer Cell. 2012 Dec 11;22(6):725-36 23201165 Cancer Res. 2012 Dec 15;72(24):6435-46 23074286 J Biol Chem. 2013 Apr 12;288(15):10241-53 23447531 Int J Cancer. 2013 Aug 1;133(3):544-55 23354685 J Biol Chem. 2000 Jan 28;275(4):2727-32 10644736 Animals Cell Differentiation Cell Line, Transformed Cell Transformation, Neoplastic genetics CpG Islands DNA Methylation Epigenesis, Genetic Epithelial-Mesenchymal Transition genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Silencing Heterografts Humans Intercellular Signaling Peptides and Proteins metabolism Mice MicroRNAs genetics metabolism Neoplasm Metastasis Neoplasms genetics metabolism pathology Neoplastic Stem Cells metabolism pathology Paracrine Communication Promoter Regions, Genetic beta Catenin metabolism PMC3776231 2013 5 01 2013 8 20 2013 9 19 6 0 2013 9 21 6 0 2014 6 24 6 0 ppublish srep02687 10.1038/srep02687 24045437 PMC3776231 23991164 2013 08 30 2014 06 15

1932-6203 8 8 2013 PLoS ONE Association between DNA methylation in the miR-328 5'-flanking region and inter-individual differences in miR-328 and BCRP expression in human placenta. e72906 10.1371/journal.pone.0072906 MicroRNA (miRNA) are non-coding small RNA that regulate gene expression. MiR-328 is reported to influence breast cancer resistance protein (BCRP) expression in cancer cells. As a large inter-individual difference in BCRP levels is observed in various human tissues, the contribution of miR-328 to these differences is of interest. We hypothesized that DNA methylation in the miR-328 promoter region is responsible for the difference in miR-328 levels, leading to inter-individual variability in BCRP levels in human placenta. The association between placental miR-328 and BCRP levels was analyzed, and then DNA methylation in the miR-328 5'-flanking region and regulatory mechanisms causing inter-individual differences in miR-328 and BCRP levels were examined. MiR-328 expression was significantly correlated with BCRP mRNA (Rs = -0.560, P < 0.01) and protein (Rs = -0.730, P < 0.01) levels. It was also up-regulated by the demethylating agent 5-aza-2'-deoxycytidine in BCRP-expressing cells. Luciferase assays with differentially methylated reporter constructs indicated that methylation in the miR-328 5'-flanking region including a predicted CpG island remarkably decreased transcriptional activity compared to that in unmethylated constructs. We selected CCAAT/enhancer binding protein α (C/EBPα), located within the predicted CpG island, by in silico analysis. To elucidate the role of C/EBPα in miR-328 expression, a chromatin immunoprecipitation assay, promoter deletion analysis, and electrophoretic mobility shift assay (EMSA) were performed. C/EBPα-binding site-truncated constructs showed significantly decreased promoter activity, and EMSA indicated that the C/EBPα-binding sites were located in the CpG island. Finally, the methylation patterns of several CpG dinucleotides proximal to two C/EBPα-binding sites in the miR-328 5'-flanking region were correlated negatively with miR-328 levels, and positively with BCRP levels in human placental samples. These results suggest that methylation patterns in the miR-328 5'-flanking region are involved in the inter-individual difference in BCRP levels in human placenta. Saito Jumpei J Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. Hirota Takeshi T Furuta Shinji S Kobayashi Daisuke D Takane Hiroshi H Ieiri Ichiro I eng Journal Article Research Support, Non-U.S. Gov't 2013 08 21

United States PLoS One 101285081 1932-6203 0 ABCG2 protein, human 0 MIRN328 microRNA, human 0 MicroRNAs 0 Neoplasm Proteins IM Nature. 2011 Oct 20;478(7369):404-7 22012398 Mol Cancer Res. 2008 Jan;6(1):151-64 18234970 Mol Pharmacol. 2008 Mar;73(3):845-54 18042733 Mol Pharmacol. 2008 Mar;73(3):949-59 18079276 Mol Pharmacol. 2008 Mar;73(3):613-5 18086804 Cancer. 2008 Mar 1;112(5):1122-30 18219662 BMC Genomics. 2011;12:529 22032438 Trends Genet. 2000 Jun;16(6):276-7 10827456 J Pharmacol Exp Ther. 2001 Jun;297(3):1137-43 11356939 Bioinformatics. 2002 Feb;18(2):333-4 11847087 Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15649-54 12429862 Mol Cancer Ther. 2002 Apr;1(6):427-34 12477055 Mol Cancer Ther. 2002 Jun;1(8):611-6 12479221 Nucleic Acids Res. 2003 Jul 1;31(13):3651-3 12824386 Int J Cancer. 2004 Mar 20;109(2):238-46 14750175 Cancer Res. 2004 Feb 15;64(4):1247-51 14973083 J Biol Chem. 2004 Jun 4;279(23):24218-25 15044468 Cancer Res. 1989 Nov 1;49(21):5829-36 2790794 Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2960-4 8464912 Nucleic Acids Res. 1998 Jan 1;26(1):362-7 9399875 Bioinformatics. 1999 Jul-Aug;15(7-8):622-30 10487870 Pharm Res. 2004 Oct;21(10):1895-903 15553238 Br J Cancer. 2012 Mar 27;106(7):1320-30 22453125 Am J Pathol. 2012 Jun;180(6):2490-503 22521303 Lung Cancer. 2012 Jul;77(1):16-23 22306127 PLoS One. 2012;7(10):e47270 23077581 Placenta. 2012 Dec;33(12):959-70 23102655 J Nutr Biochem. 2013 Jan;24(1):282-8 22901689 Acta Biochim Pol. 2012;59(4):467-74 23173124 Mol Pharmacol. 2013 Feb;83(2):399-405 23166305 Drug Metab Dispos. 2005 Jan;33(1):94-101 15475413 Clin Exp Pharmacol Physiol. 2006 Jan-Feb;33(1-2):58-65 16445700 Mol Cell Biol. 2006 Nov;26(22):8572-85 16954373 Blood. 2006 Dec 1;108(12):3881-9 16917002 Cancer Sci. 2007 Feb;98(2):231-9 17297656 Placenta. 2007 Apr;28 Suppl A:S116-20 17275084 PLoS Comput Biol. 2007 Mar 9;3(3):e37 17352530 Pharm Res. 2007 Jun;24(6):1108-17 17373578 Clin Sci (Lond). 2007 Jul;113(1):1-13 17536998 Cell Cycle. 2007 Jun 15;6(12):1455-9 17581274 Mol Pharmacol. 2007 Oct;72(4):967-75 17644650 FASEB J. 2007 Nov;21(13):3592-605 17595345 Drug Metab Dispos. 2007 Dec;35(12):2154-8 17785426 Br J Cancer. 2008 May 6;98(9):1515-24 18382425 Mol Cancer Ther. 2008 Jul;7(7):2152-9 18645025 Pharm Res. 2008 Jun;25(6):1244-55 18202831 Biochem Pharmacol. 2008 Sep 1;76(5):582-8 18619946 Lab Invest. 2009 Mar;89(3):327-36 19139722 Mol Pharmacol. 2009 Jun;75(6):1374-9 19270061 Mol Pharmacol. 2009 Oct;76(4):702-9 19570947 PLoS One. 2009;4(10):e7389 19838307 PLoS One. 2009;4(12):e8445 20041160 Biochem Pharmacol. 2010 Mar 15;79(6):817-24 19883630 Clin Cancer Res. 2010 Feb 15;16(4):1119-28 20145172 Brain Pathol. 2010 May;20(3):539-50 19775293 FEBS Lett. 2010 Aug 4;584(15):3392-7 20600004 Mol Cancer Ther. 2010 Aug;9(8):2265-75 20647341 Int J Cancer. 2010 Oct 15;127(8):1785-94 20099276 Med Sci Monit. 2010 Oct;16(10):HY27-30 20885358 J Biol Chem. 2010 Oct 8;285(41):31100-6 20705611 Drug Metab Rev. 2011 Feb;43(1):53-68 20854129 Biochem Pharmacol. 2011 Mar 15;81(6):783-92 21219875 Clin Cancer Res. 2011 Mar 15;17(6):1287-96 21138856 PLoS One. 2011;6(6):e21210 21698265 Toxicol Sci. 2011 Sep;123(1):1-14 21715665 ATP-Binding Cassette Transporters genetics Cell Line, Tumor CpG Islands DNA Methylation Female Humans MicroRNAs genetics Neoplasm Proteins genetics Placenta metabolism Pregnancy Transcription, Genetic PMC3749162 2013 2013 4 12 2013 7 15 2013 8 21 2013 8 31 6 0 2013 8 31 6 0 2014 6 16 6 0 epublish 10.1371/journal.pone.0072906 PONE-D-13-15093 23991164 PMC3749162 23979134 2013 10 07 2013 12 03 2014 10 09

1083-351X 288 40 2013 Oct 4 J. Biol. Chem. MicroRNA-433 inhibits liver cancer cell migration by repressing the protein expression and function of cAMP response element-binding protein. 28893-9 10.1074/jbc.M113.502682 We show for the first time that potent microRNA-433 (miR-433) inhibition of expression of the cAMP response element-binding protein CREB1 represses hepatocellular carcinoma (HCC) cell migration. We identified a miR-433 seed match region in human and mouse CREB1 3'-UTRs. Overexpression of miR-433 markedly decreased human CREB1 3'-UTR reporter activity, and the inhibitory effect of miR-433 was alleviated upon mutation of its binding site. Ectopic expression of miR-433 reduced CREB1 protein levels in a variety of human and mouse cancer cells, including HeLa, Hepa1, Huh7, and HepG2. Human CREB1 protein levels in highly invasive MHCC97H cells were diminished by expression of miR-433 but were induced by miR-433 antagomir (anti-miR-433). The expression of mouse CREB1 protein negatively correlated with miR-433 levels in nuclear receptor Shp(-/-) liver tissues and liver tumors compared with wild-type mice. miR-433 exhibited a significant repression of MHCC97H cell migration, which was reversed by anti-miR-433. Overexpressing miR-433 inhibited focus formation dramatically, demonstrating that miR-433 may exert a tumor suppressor function. Knockdown of CREB1 by siRNAs impeded MHCC97H cell migration and invasion and antagonized the effect of anti-miR-433. Interestingly, CREB1 siRNA decreased MHCC97H cell proliferation, which was not influenced by anti-miR-433. Overexpressing CREB1 decreased the inhibitory activity of miR-433. The CpG islands surrounding miR-433 were hypermethylated, and the DNA methylation agent 5'-aza-2'-deoxycytidine, but not the histone deacetylase inhibitor trichostatin A, drastically stimulated the expression of miR-433 and miR-127 in HCC cells. The latter is clustered with miR-433. The results reveal a critical role of miR-433 in mediating HCC cell migration via CREB1. Yang Zhihong Z From the Departments of Medicine and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, and. Tsuchiya Hiroyuki H Zhang Yuxia Y Hartnett M Elizabeth ME Wang Li L eng DK080440 DK NIDDK NIH HHS United States P30 EY014800 EY NEI NIH HHS United States P30CA042014 CA NCI NIH HHS United States R01 EY017011 EY NEI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2013 08 26

United States J Biol Chem 2985121R 0021-9258 0 CREB1 protein, human 0 Creb1 protein, mouse 0 Cyclic AMP Response Element-Binding Protein 0 MIRN433 microRNA, human 0 MicroRNAs 0 Mirn433 microRNA, mouse 0 RNA, Small Interfering IM PLoS One. 2009;4(11):e7829 19946636 PLoS One. 2009;4(9):e6880 19721712 Hum Mol Genet. 2010 May 15;19(10):2015-27 20181727 Aliment Pharmacol Ther. 2010 Aug;32(3):487-97 20497147 J Biol Chem. 2010 Aug 6;285(32):24871-81 20516075 Nucleic Acids Res. 2010 Sep;38(16):5366-83 20423907 Cell Metab. 2011 Feb 2;13(2):125-37 21284980 Nat Rev Mol Cell Biol. 2011 Mar;12(3):141-51 21346730 FEBS Lett. 2011 May 6;585(9):1269-75 21459093 J Biol Chem. 2011 Aug 26;286(34):29635-43 21725089 Lancet Oncol. 2010 Feb;11(2):136-46 20022810 Biochem Biophys Res Commun. 2011 Dec 9;416(1-2):135-9 22100809 Int J Biochem Cell Biol. 2012 Jan;44(1):33-45 22004992 Biochem Biophys Res Commun. 2012 Jan 13;417(2):744-6 22197810 World J Gastroenterol. 2012 Oct 14;18(38):5442-53 23082062 Leukemia. 2013 Feb;27(2):344-52 22864358 Cancer Res. 2004 Feb 15;64(4):1338-46 14973073 Nature. 1999 Mar 11;398(6723):165-9 10086359 Trends Biochem Sci. 1999 Jul;24(7):281-5 10390618 J Cell Physiol. 2006 Feb;206(2):411-9 16110470 FEBS J. 2007 Jul;274(13):3224-32 17565603 Gastroenterology. 2008 Mar;134(3):793-802 18325392 Hepatology. 2008 Jul;48(1):289-98 18537191 Nucleic Acids Res. 2008 Oct;36(18):5727-35 18776219 PLoS One. 2008;3(10):e3574 18974780 Cancer Res. 2009 Mar 15;69(6):2471-8 19258499 J Exp Clin Cancer Res. 2009;28:82 19531230 J Biol Chem. 2009 Nov 13;284(46):31921-7 19723635 Acetylation Animals Base Sequence Carcinoma, Hepatocellular genetics pathology Cell Line, Tumor Cell Movement genetics Cell Proliferation Cyclic AMP Response Element-Binding Protein genetics metabolism DNA Methylation genetics Gene Expression Regulation, Neoplastic Humans Liver Neoplasms genetics pathology Mice MicroRNAs metabolism Molecular Sequence Data RNA, Small Interfering metabolism PMC3789984 Cell Migration HCC Liver Cancer MicroRNA Post-translational Modification Translation Regulation 2013 8 26 2013 8 28 6 0 2013 8 28 6 0 2013 12 16 6 0 ppublish 23979134 M113.502682 10.1074/jbc.M113.502682 PMC3789984 23961262 2013 08 20 2013 08 20 2013 08 23

1477-3163 12 2013 J Carcinog Restoration of the methylation status of hypermethylated gene promoters by microRNA-29b in human breast cancer: A novel epigenetic therapeutic approach. 15 10.4103/1477-3163.115720 It is well established that transcriptional silencing of critical tumor-suppressor genes by DNA methylation is a fundamental component in the initiation of breast cancer. However, the involvement of microRNAs (miRNAs) in restoring abnormal DNA methylation patterns in breast cancer is not well understood. Therefore, we investigated whether miRNA-29b, due to its complimentarity to the 3'- untranslated region of DNA methyltransferase 3A (DNMT3A) and DNMT3B, could restore normal DNA methylation patterns in human breast cancers and breast cancer cell lines. We demonstrated that transfection of pre-miRNA-29b into less aggressive MCF-7 cells, but not MDA-MB-231 mesenchymal cells, inhibited cell proliferation, decreased DNMT3A and DNMT3B messenger RNA (mRNA), and decreased promoter methylation status of ADAM23 , CCNA1, CCND2, CDH1, CDKN1C, CDKN2A, HIC1, RASSF1, SLIT2, TNFRSF10D, and TP73 tumor-suppressor genes. Using methylation polymerase chain reaction (PCR) arrays and real-time PCR, we also demonstrated that the methylation status of several critical tumor-suppressor genes increased as stage of breast disease increased, while miRNA-29b mRNA levels were significantly decreased in breast cancers versus normal breast. This increase in methylation status was accompanied by an increase in DNMT1 and DNMT3B mRNA in advanced stage of human breast cancers and in MCF-7, MDA-MB-361, HCC70, Hs-578T, and MDA-MB-231 breast cancer cells as compared to normal breast specimens and MCF-10-2A, a non-tumorigenic breast cell line, respectively. Our findings highlight the potential for a new epigenetic approach in improving breast cancer therapy by targeting DNMT3A and DNMT3B through miRNA-29b in non-invasive epithelial breast cancer cells. Starlard-Davenport Athena A Office of the Associate Director for Regulatory Activities, Jefferson, AR 72079, USA. Kutanzi Kristi K Tryndyak Volodymyr V Word Beverly B Lyn-Cook Beverly B eng Journal Article 2013 07 26

India J Carcinog 101153623 1477-3163 PMC3746452 Breast cancer DNA methylation DNA methyltransferase1 DNA methyltransferases 3A DNA methyltransferases 3B microRNA-29b 2013 2012 8 22 2012 12 13 2013 7 26 2013 8 21 6 0 2013 8 21 6 0 2013 8 21 6 1 epublish 10.4103/1477-3163.115720 JC-12-15 23961262 PMC3746452 23959088 2014 04 17

1559-2308 9 1 2014 Jan 1 Epigenetics microRNA-199a-3p, DNMT3A, and aberrant DNA methylation in testicular cancer. 119-28 10.4161/epi.25799 It was previously demonstrated that miR-199a was downregulated in testicular germ cell tumor (TGCT), probably due to hypermethylation of its promoter. Further study found that re-expression of miR-199a in testicular cancer cells (NT2) led to suppression of cell growth, cancer migration, invasion and metastasis. More detailed analyses showed that these properties of miR-199a could be assigned to miR-199a-5p, one of its two derivatives. The biological role of the other derivative, miR-199a-3p in TGCT, remains largely uncharacterized. In this report, we identified DNA (cytosine-5)-methyltransferase 3A (DNMT3A), the de novo methyltransferase, as a direct target of miR-199a-3p using a 3'-UTR reporter assay. Transient expression of miR-199a-3p in NT2 cells led to decrease, while knocking down of miR-199a-3p in a normal human testicular cell line (HT) led to elevation, of DNMT3A2 (DNMT3A gene isoform 2) mRNA and protein levels. In clinical samples, DNMT3A2 was significantly overexpressed in malignant testicular tumor, and the expression of DNMT3A2 was inversely correlated with the expression of miR-199a-3p. However, DNMT3A did not affect miR-199a expression in NT2 cells. Further characterization of miR-199a-3p revealed that it negatively regulated DNA methylation, partly through targeting DNMT3A. Overexpression of miR-199a-3p restored the expression of APC and MGMT tumor-suppressor genes in NT2 cells by affecting DNA methylation of their promoter regions. Our studies demonstrated the deregulation of miR-199a-3p expression in TGCT may provide novel mechanistic insights into TGCT carcinogenesis and suggested a potentially therapeutic use of synthetic miR-199a-3p oligonucleotides as effective hypomethylating compounds in the treatment of TGCT. Chen Bi-Feng BF Key Laboratory for Regenerative Medicine; Ministry of Education; School of Biomedical Sciences; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong, P.R. China. Gu Shen S Key Laboratory for Regenerative Medicine; Ministry of Education; School of Biomedical Sciences; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong, P.R. China. Suen Yick-Keung YK Key Laboratory for Regenerative Medicine; Ministry of Education; School of Biomedical Sciences; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong, P.R. China. Li Lu L Key Laboratory for Regenerative Medicine; Ministry of Education; School of Biomedical Sciences; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong, P.R. China. Chan Wai-Yee WY Key Laboratory for Regenerative Medicine; Ministry of Education; School of Biomedical Sciences; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong, P.R. China. eng Journal Article Research Support, Non-U.S. Gov't 2013 08 19

United States Epigenetics 101265293 1559-2294 IM PMC3928174 [Available on 01/01/15] DNA methylation DNMT3A miR-199a-3p testicular cancer 2013 8 19 2013 8 21 6 0 2015 1 1 0 0 2013 8 21 6 0 2013 8 21 6 0 ppublish 23959088 25799 10.4161/epi.25799 PMC3928174 23942619 2014 07 07

1435-5922 49 7 2014 Jul J. Gastroenterol. Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk. 1135-44 10.1007/s00535-013-0861-7 Metachronous gastric cancer (GC) can develop after endoscopic resection of GC and cannot be predicted based on clinical signature. Aberrant DNA methylation in noncancerous gastric mucosa is strongly implicated in gastric carcinogenesis and could be a useful biomarker of GC risk. We evaluated the clinical utility of DNA methylation as a biomarker of metachronous GC risk. We carried out scheduled follow-up endoscopy in 129 patients after curative endoscopic resection of GC. Biopsy specimens were collected from noncancerous mucosa in the gastric antrum and body, after which quantitative methylation analysis of miR-34b/c, SFRP1, SFRP2, SFRP5, DKK2 and DKK3 was carried out using bisulfite pyrosequencing. The utility of the methylation for predicting the risk of metachronous GC development was assessed using Kaplan-Meier and Cox proportional hazards model analyses. During the follow-up period, 17 patients (13%) developed metachronous GCs. The cumulative incidence of metachronous GC was significantly higher among patients with elevated miR-34b/c, SFRP2 and DKK2 methylation in their gastric body. MiR-34b/c showed the strongest association with the risk of metachronous GC, and the cumulative incidence of metachronous GC was much higher in the high-miR-34b/c-methylation group than the low-methylation group. Multivariate analysis adjusted for age, sex, H. pylori status and pathological findings showed miR-34b/c methylation in gastric body to be an independent predictor of metachronous GC risk. Our results suggest that methylation of miR-34b/c in the mucosa of the noncancerous gastric body may be a useful biomarker for predicting the risk of metachronous GC. Suzuki Ryo R Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University, S1, W16, Chuo-Ku, Sapporo, 060-8543, Japan. Yamamoto Eiichiro E Nojima Masanori M Maruyama Reo R Yamano Hiro-O HO Yoshikawa Kenjiro K Kimura Tomoaki T Harada Taku T Ashida Masami M Niinuma Takeshi T Sato Akiko A Nosho Katsuhiko K Yamamoto Hiroyuki H Kai Masahiro M Sugai Tamotsu T Imai Kohzoh K Suzuki Hiromu H Shinomura Yasuhisa Y eng Journal Article Research Support, Non-U.S. Gov't 2013 08 13

Japan J Gastroenterol 9430794 0944-1174 IM Gut. 2009 Mar;58(3):331-6 19001058 Pharmacogenomics. 2008 Dec;9(12):1917-28 19072648 Gut. 2013 Oct;62(10):1425-32 22914298 Gut. 2013 Nov;62(11):1536-46 22936674 Int J Cancer. 2009 May 15;124(10):2367-74 19165869 Gastroenterology. 2009 Nov;137(5):1641-8.e1-2 19664631 J Gastroenterol. 2010;45(1):37-44 19821005 Cancer Res. 2010 Feb 15;70(4):1430-40 20124475 Gastroenterology. 2010 May;138(5):1836-44 20044995 Carcinogenesis. 2010 Dec;31(12):2066-73 20924086 Digestion. 2011;83(4):241-9 21273772 Gastrointest Endosc. 2012 Jan;75(1):39-46 22018552 Clin Cancer Res. 2012 Feb 15;18(4):923-9 22205689 Gastroenterology. 2012 Sep;143(3):550-63 22796521 Cancer Prev Res (Phila). 2012 Oct;5(10):1203-12 22961779 Gastric Cancer. 2012 Oct;15(4):382-8 22237657 Mol Oncol. 2012 Dec;6(6):567-78 22902148 Gut. 2001 Feb;48(2):225-9 11156645 N Engl J Med. 2001 Sep 13;345(11):784-9 11556297 Gut. 2003 Apr;52(4):502-6 12631658 JAMA. 2004 Jan 14;291(2):187-94 14722144 Am J Surg Pathol. 1996 Oct;20(10):1161-81 8827022 Am J Pathol. 1999 Mar;154(3):951-60 10079274 J Clin Oncol. 2005 Jul 10;23(20):4490-8 16002839 Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):989-95 16467114 Gut. 2006 Apr;55(4):463-8 16428266 Gastric Cancer. 2006;9(2):93-8 16767364 Gut. 2006 Nov;55(11):1545-52 16603635 Cancer Epidemiol Biomarkers Prev. 2006 Nov;15(11):2317-21 17119066 Gastrointest Endosc. 2006 Dec;64(6):877-83 17140890 Cell. 2007 Feb 23;128(4):683-92 17320506 Am J Gastroenterol. 2007 Jul;102(7):1361-71 17509026 Oncogene. 2007 Jul 12;26(32):4699-713 17297461 Carcinogenesis. 2007 Dec;28(12):2459-66 17675336 Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2555-64 18842996 Lancet. 2008 Aug 2;372(9636):392-7 18675689 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Gastroenterology. 2013 Jan;144(1):122-133.e9 23058321 PMC4083150 2013 4 8 2013 7 25 2013 8 13 2013 8 15 6 0 2013 8 15 6 0 2013 8 15 6 0 ppublish 10.1007/s00535-013-0861-7 23942619 PMC4083150 23933257 2013 08 19 2014 06 05

2211-1247 4 3 2013 Aug 15 Cell Rep Integrating genomic, epigenomic, and transcriptomic features reveals modular signatures underlying poor prognosis in ovarian cancer. 542-53 10.1016/j.celrep.2013.07.010 S2211-1247(13)00357-4 Ovarian cancer has a poor prognosis, with different outcomes for different patients. The mechanism underlying this poor prognosis and heterogeneity is not well understood. We have developed an unbiased, adaptive clustering approach to integratively analyze ovarian cancer genome-wide gene expression, DNA methylation, microRNA expression, and copy number alteration profiles. We uncovered seven previously uncategorized subtypes of ovarian cancer that differ significantly in median survival time. We then developed an algorithm to uncover molecular signatures that distinguish cancer subtypes. Surprisingly, although the good-prognosis subtypes seem to have not been functionally selected, the poor-prognosis ones clearly have been. One subtype has an epithelial-mesenchymal transition signature and a cancer hallmark network, whereas the other two subtypes are enriched for a network centered on SRC and KRAS. Our results suggest molecular signatures that are highly predictive of clinical outcomes and spotlight "driver" genes that could be targeted by subtype-specific treatments. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved. Zhang Wei W Key Laboratory of Computational Biology, Chinese Academy of Sciences-Max Planck Partner Institute for Computational Biology, Shanghai 200031, China. Liu Yi Y Sun Na N Wang Dan D Boyd-Kirkup Jerome J Dou Xiaoyang X Han Jing-Dong Jackie JD eng Journal Article Research Support, Non-U.S. Gov't 2013 08 08

United States Cell Rep 101573691 IM Cluster Analysis Epigenomics methods Female Gene Expression Profiling methods Genomics methods Humans Ovarian Neoplasms genetics metabolism Prognosis Proportional Hazards Models Survival Analysis 2013 3 2 2013 5 18 2013 7 9 2013 8 8 2013 8 13 6 0 2013 8 13 6 0 2014 6 6 6 0 ppublish S2211-1247(13)00357-4 10.1016/j.celrep.2013.07.010 23933257 23900077 2013 09 25 2014 04 02

1460-2083 22 R1 2013 Oct 15 Hum. Mol. Genet. The evolving epigenome. R1-6 10.1093/hmg/ddt348 Epigenetic studies include the investigation of DNA methylation, histone modifications, chromatin remodeling and gene regulation by noncoding RNAs (ncRNAs). Epigenetic alterations are critical for early developmental processes, the silencing of the inactive X-chromosome and tissue-specific gene regulation. A comprehensive picture of epigenetic patterns in normal cells is now emerging; these patterns are disturbed in human diseases such as cancer. In this review, we highlight some of the most recent advances and discoveries in the field. First, while DNA methylation is known for many years, we are just beginning to learn about novel modifications of the DNA such as 5-hydroxymethylation and the enzymes that establish and remove these marks (e.g. TET1, TET2, TET3). Furthermore, altered epigenetic patterns in diseases might be linked to recurrent mutations within enzymes required for the establishment, maintenance and editing of these patterns. Examples are mutations in the gene encoding chromatin remodeling factor SMARCB1 in rhabdoid tumors or mutations in one of the three histone H3.3-encoding genes, H3F3A, in pediatric glioblastomas. A further focus in this review will be on recent findings in the field of ncRNAs as exemplified by the long noncoding RNA CTBP1-AS involved in prostate cancer and circular RNA CDR1as which captures and negatively regulates microRNA mir-7. Finally, we will highlight some of the novel technologies that have recently emerged in the field and will help in the profiling of disease genomes by allowing the use of small cell numbers and a higher resolution. Weichenhan Dieter D Plass Christoph C eng Journal Article Research Support, Non-U.S. Gov't Review 2013 07 29

England Hum Mol Genet 9208958 0964-6906 0 Chromosomal Proteins, Non-Histone 0 DNA-Binding Proteins 0 Histones 0 MIRN7 microRNA, human 0 MicroRNAs 0 RNA, Untranslated 0 SMARCB1 protein, human 0 Transcription Factors 6R795CQT4H 5-Methylcytosine IM 5-Methylcytosine metabolism Chromosomal Proteins, Non-Histone genetics Computational Biology DNA Methylation DNA-Binding Proteins genetics Epigenesis, Genetic Gene Expression Regulation, Neoplastic Genome, Human Histones genetics metabolism Humans Male MicroRNAs genetics Organ Specificity Prostatic Neoplasms genetics metabolism RNA, Untranslated genetics Transcription Factors genetics 2013 7 29 2013 8 7 2013 8 1 6 0 2013 8 1 6 0 2014 4 3 6 0 ppublish ddt348 10.1093/hmg/ddt348 23900077 23895687 2013 09 16 2014 04 04

1875-533X 20 32 2013 Curr. Med. Chem. Medicinal chemistry of the epigenetic diet and caloric restriction. 4050-9 The pronounced effects of the epigenetic diet (ED) and caloric restriction (CR) have on epigenetic gene regulation have been documented in many pre-clinical and clinical studies. Understanding epigenetics is of high importance because of the concept that external factors such as nutrition and diet may possess the ability to alter gene expression without modifying the DNA sequence. The ED introduces bioactive medicinal chemistry compounds such as sulforaphane (SFN), curcumin (CCM), epigallocatechin gallate (EGCG) and resveratrol (RSV) that are thought to aid in extending the human lifespan. CR, although similar to ED in the target of longevity, mildly reduces the total daily calorie intake while concurrently providing all beneficial nutrients. Both CR and ED may act as epigenetic modifiers to slow the aging process through histone modification, DNA methylation, and by modulating microRNA expression. CR and ED have been proposed as two important mechanisms that modulate and potentially slow the progression of age-related diseases such as cardiovascular disease (CVD), cancer, obesity, Alzheimer's and osteoporosis to name a few. While many investigators have examined CR and ED as separate entities, this review will primarily focus on both as they relate to age-related diseases, their epigenetic effects and their medicinal chemistry. Martin S L SL CH175, 1300 University Boulevard, Birmingham, AL 35294-1170 USA. trygve@uab.edu. Hardy T M TM Tollefsbol T O TO eng CA 129415 CA NCI NIH HHS United States R01 CA129415 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

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discussion 172 2520283 Ann Rheum Dis. 1994 Sep;53(9):565-8 7979593 Am J Physiol. 1995 May;268(5 Pt 1):E941-8 7762649 Toxicol Pathol. 1996 Nov-Dec;24(6):742-5 8994305 Am J Epidemiol. 1998 Mar 15;147(6):516-22 9521177 J Gerontol A Biol Sci Med Sci. 1998 Nov;53(6):B443-8 9823741 Epidemiology. 1999 Mar;10(2):161-6 10069252 MMWR Morb Mortal Wkly Rep. 1999 Apr 2;48(12):241-3 10220250 Drugs Today (Barc). 2005 Mar;41(3):205-18 15883617 Mech Ageing Dev. 2005 Sep;126(9):913-22 15885745 Rheumatology (Oxford). 2005 Dec;44 Suppl 4:iv36-iv40 16306481 Mech Ageing Dev. 2006 Jan;127(1):1-7 16226298 Nucleic Acids Res. 2005;33(21):6850-60 16326864 Aging drug effects Anticarcinogenic Agents pharmacology Caloric Restriction Catechin analogs & derivatives pharmacology Chemistry, Pharmaceutical Curcumin pharmacology Epigenesis, Genetic drug effects physiology Humans Isothiocyanates pharmacology Stilbenes pharmacology NIHMS538657 PMC3873820 2012 12 11 2013 6 12 2013 7 23 2013 7 31 6 0 2013 7 31 6 0 2014 4 5 6 0 ppublish CMC-EPUB-54471 23895687 PMC3873820 NIHMS538657 23857059 2013 07 16 2014 02 11

1422-0067 14 7 2013 Int J Mol Sci miR-29 represses the activities of DNA methyltransferases and DNA demethylases. 14647-58 10.3390/ijms140714647 Members of the microRNA-29 (miR-29) family directly target the DNA methyltransferases, DNMT3A and DNMT3B. Disturbances in the expression levels of miR-29 have been linked to tumorigenesis and tumor aggressiveness. Members of the miR-29 family are currently thought to repress DNA methylation and suppress tumorigenesis by protecting against de novo methylation. Here, we report that members of the miR-29 family repress the activities of DNA methyltransferases and DNA demethylases, which have opposing roles in control of DNA methylation status. Members of the miR-29 family directly inhibited DNA methyltransferases and two major factors involved in DNA demethylation, namely tet methylcytosine dioxygenase 1 (TET1) and thymine DNA glycosylase (TDG). Overexpression of miR-29 upregulated the global DNA methylation level in some cancer cells and downregulated DNA methylation in other cancer cells, suggesting that miR-29 suppresses tumorigenesis by protecting against changes in the existing DNA methylation status rather than by preventing de novo methylation of DNA. Morita Sumiyo S Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan. msumiyo@gunma-u.ac.jp Horii Takuro T Kimura Mika M Ochiya Takahiro T Tajima Shoji S Hatada Izuho I eng Journal Article Research Support, Non-U.S. Gov't 2013 07 12

Switzerland Int J Mol Sci 101092791 1422-0067 0 3' Untranslated Regions 0 DNA-Binding Proteins 0 MIRN29 microRNA, human 0 MicroRNAs 0 Proto-Oncogene Proteins 0 RNA, Messenger 0 TET1 protein, human EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA methyltransferase 3A EC 2.1.1.37 DNA methyltransferase 3B EC 3.2.2.- Thymine DNA Glycosylase IM Science. 2009 May 15;324(5929):930-5 19372391 Blood. 2010 Apr 1;115(13):2630-9 20086245 Nature. 2010 Dec 9;468(7325):839-43 21057493 N Engl J Med. 2010 Dec 16;363(25):2424-33 21067377 Science. 2011 Sep 2;333(6047):1300-3 21778364 Science. 2011 Sep 2;333(6047):1303-7 21817016 J Biol Chem. 2011 Oct 14;286(41):35334-8 21862836 Int J Oncol. 2012 Jun;40(6):2097-103 22426940 Mol Cancer Ther. 2012 May;11(5):1166-73 22402125 Cell. 1999 Oct 29;99(3):247-57 10555141 Science. 2001 Dec 21;294(5551):2536-9 11719692 Nat Rev Cancer. 2004 Feb;4(2):143-53 14732866 Dev Genet. 1998;22(2):132-40 9581285 PLoS Biol. 2004 Nov;2(11):e363 15502875 Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3336-41 15728362 Trends Biochem Sci. 2006 Feb;31(2):89-97 16403636 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Cancer Cell. 2006 Mar;9(3):189-98 16530703 Exp Cell Res. 2006 Jul 1;312(11):1989-95 16624287 Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15805-10 17890317 Nature. 2012 Aug 30;488(7413):660-4 22895193 3' Untranslated Regions Cell Line, Tumor DNA (Cytosine-5-)-Methyltransferase genetics metabolism DNA Methylation DNA-Binding Proteins genetics metabolism Humans MicroRNAs metabolism Proto-Oncogene Proteins genetics metabolism RNA, Messenger metabolism Thymine DNA Glycosylase genetics metabolism PMC3742264 2013 5 29 2013 6 25 2013 6 25 2013 7 17 6 0 2013 7 17 6 0 2014 2 12 6 0 epublish ijms140714647 10.3390/ijms140714647 23857059 PMC3742264 23813567 2013 07 04 2013 09 16

1098-2280 54 6 2013 Jul Environ. Mol. Mutagen. Aberrant DNA methylation of miR-219 promoter in long-term night shiftworkers. 406-13 10.1002/em.21790 The idea that shiftwork may be carcinogenic in humans has gained widespread attention since the pioneering work linking shiftwork to breast cancer over two decades ago. However, the biomolecular consequences of long-term shiftwork exposure have not been fully explored. In this study, we performed a genome-wide CpG island methylation assay of microRNA (miRNA) promoters in long-term night shiftworkers and day workers. This analysis indicated that 50 CpG loci corresponding to 31 miRNAs were differentially methylated in night shiftworkers compared to day workers, including the circadian-relevant miR-219, the expression of which has been implicated in several cancers. A genome-wide expression microarray assay was carried out in a miR-219-overexpressed MCF-7 breast cancer cell line, which identified 319 differentially expressed transcripts. The identified transcriptional targets were analyzed for network and functional interrelatedness using the Ingenuity Pathway Analysis (IPA) software. Overexpression of miR-219 in MCF-7 breast cancer cells resulted in accentuated expression of apoptosis- and proliferation-related anti-viral immunodulators of the Jak-STAT and NF-κβ pathways. These findings suggest that long-term night shiftwork exposure may lead to the methylation-dependent downregulation of miR-219, which may in turn lead to the downregulation of immunomediated antitumor activity and increased breast cancer risk. © 2013 Wiley Periodicals, Inc. Shi Fengqin F Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA. Chen Xinyi X Fu Alan A Hansen Johnni J Stevens Richard R Tjonneland Anne A Vogel Ulla B UB Zheng Tongzhang T Zhu Yong Y eng ES018915 ES NIEHS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2013 06 27

United States Environ Mol Mutagen 8800109 0893-6692 0 MIRN219 microRNA, human 0 MicroRNAs 0 NF-kappa B IM Apoptosis genetics Breast Neoplasms genetics Cell Line, Tumor CpG Islands genetics DNA Methylation Female Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Humans MicroRNAs genetics Middle Aged NF-kappa B metabolism Occupational Diseases genetics Promoter Regions, Genetic Risk Work Schedule Tolerance breast cancer methylation miR-219 microRNAs shiftwork 2013 3 13 2013 4 29 2013 5 3 2013 6 27 2013 7 2 6 0 2013 7 3 6 0 2013 9 17 6 0 ppublish 23813567 10.1002/em.21790 23722552 2013 07 17 2014 02 06

1538-7445 73 14 2013 Jul 15 Cancer Res. Integration of high-resolution methylome and transcriptome analyses to dissect epigenomic changes in childhood acute lymphoblastic leukemia. 4323-36 10.1158/0008-5472.CAN-12-4367 B-cell precursor acute lymphoblastic leukemia (pre-B ALL) is the most common pediatric cancer. Although the genetic determinants underlying disease onset remain unclear, epigenetic modifications including DNA methylation are suggested to contribute significantly to leukemogenesis. Using the Illumina 450K array, we assessed DNA methylation in matched tumor-normal samples of 46 childhood patients with pre-B ALL, extending single CpG-site resolution analysis of the pre-B ALL methylome beyond CpG-islands (CGI). Unsupervised hierarchical clustering of CpG-site neighborhood, gene, or microRNA (miRNA) gene-associated methylation levels separated the tumor cohort according to major pre-B ALL subtypes, and methylation in CGIs, CGI shores, and in regions around the transcription start site was found to significantly correlate with transcript expression. Focusing on samples carrying the t(12;21) ETV6-RUNX1 fusion, we identified 119 subtype-specific high-confidence marker CpG-loci. Pathway analyses linked the CpG-loci-associated genes with hematopoiesis and cancer. Further integration with whole-transcriptome data showed the effects of methylation on expression of 17 potential drivers of leukemogenesis. Independent validation of array methylation and sequencing-derived transcript expression with Sequenom Epityper technology and real-time quantitative reverse transcriptase PCR, respectively, indicates more than 80% empirical accuracy of our genome-wide findings. In summary, genome-wide DNA methylation profiling enabled us to separate pre-B ALL according to major subtypes, to map epigenetic biomarkers specific for the t(12;21) subtype, and through a combined methylome and transcriptome approach to identify downstream effects on candidate drivers of leukemogenesis. ©2013 AACR. Busche Stephan S Department of Human Genetics, McGill University, Montréal, Canada. Ge Bing B Vidal Ramon R Spinella Jean-François JF Saillour Virginie V Richer Chantal C Healy Jasmine J Chen Shu-Huang SH Droit Arnaud A Sinnett Daniel D Pastinen Tomi T eng Journal Article Research Support, Non-U.S. Gov't 2013 05 30

United States Cancer Res 2984705R 0008-5472 0 Core Binding Factor Alpha 2 Subunit 0 ETS translocation variant 6 protein 0 MicroRNAs 0 Proto-Oncogene Proteins c-ets 0 RUNX1 protein, human 0 Repressor Proteins IM Adolescent Child Child, Preschool Core Binding Factor Alpha 2 Subunit genetics CpG Islands DNA Methylation Epigenesis, Genetic Epigenomics methods Female Gene Expression Gene Expression Profiling methods Humans Male MicroRNAs genetics Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics Proto-Oncogene Proteins c-ets genetics Repressor Proteins genetics Transcription Initiation Site Transcriptome 2013 5 30 2013 7 5 2013 6 1 6 0 2013 6 1 6 0 2014 2 7 6 0 ppublish 0008-5472.CAN-12-4367 10.1158/0008-5472.CAN-12-4367 23722552 23696878 2013 05 22 2013 12 23 2014 08 12

1932-6203 8 5 2013 PLoS ONE PEpiD: a prostate epigenetic database in mammals. e64289 10.1371/journal.pone.0064289 Epigenetic mechanisms play key roles in initiation and progression of prostate cancer by changing gene expression. The Prostate Epigenetic Database (PEpiD: http://wukong.tongji.edu.cn/pepid) archives the three extensively characterized epigenetic mechanisms DNA methylation, histone modification, and microRNA implicated in prostate cancer of human, mouse, and rat. PEpiD uses a distinct color scheme to present the three types of epigenetic data and provides a user-friendly interface for flexible query. The retrieved information includes Refseq ID, gene symbol, gene alias, genomic loci of epigenetic changes, tissue source, experimental method, and supportive references. The change of histone modification (hyper or hypo) and the corresponding gene expression change (up or down) are also indicated. A graphic view of DNA methylation with exon-intron structure and predicted CpG islands is provided as well. Moreover, the prostate-related ENCODE tracks (DNA methylation, histone modifications, chromatin remodelers), and other key transcription factors with reported roles in prostate are displayed in the browser as well. The reversibility of epigenetic aberrations has made them potential markers for diagnosis and prognosis, and targets for treatment of cancers. This curated information will improve our understanding of epigenetic mechanisms of gene regulation in prostate cancer, and serve as an important resource for epigenetic research in prostate cancer. Shi Jiejun J Shanghai Key Laboratory of Signaling and Disease Research, Department of Bioinformatics, Shanghai Tenth People's Hospital, The School of Life Sciences and Technology, Tongji University, Shanghai, China. Hu Jian J Zhou Qing Q Du Yanhua Y Jiang Cizhong C eng Journal Article Research Support, Non-U.S. Gov't 2013 05 16

United States PLoS One 101285081 1932-6203 0 Histones IM Cancer Res. 2013 Mar 1;73(5):1570-80 23269278 Nucleic Acids Res. 2002 Jan 1;30(1):218-20 11752298 Nucleic Acids Res. 2003 Jan 1;31(1):75-7 12519951 Nucleic Acids Res. 2003 Jan 1;31(1):291-3 12520005 J Mol Biol. 1987 Jul 20;196(2):261-82 3656447 Cancer Cells. 1991 Oct;3(10):383-90 1777359 Cancer Res. 1998 Dec 1;58(23):5310-4 9850055 BMC Bioinformatics. 2006;7:446 17038168 Clin Cancer Res. 2007 May 1;13(9):2541-8 17473182 Cancer Res. 2007 Jul 1;67(13):6130-5 17616669 Nucleic Acids Res. 2008 Jan;36(Database issue):D842-6 17932060 Nature. 2008 Aug 7;454(7205):711-5 18685699 Nucleic Acids Res. 2009 Jan;37(Database issue):D98-104 18927107 Nucleic Acids Res. 2010 Jan;38(Database issue):D149-54 19892823 Nucleic Acids Res. 2011 Jan;39(Database issue):D980-5 20880996 Nucleic Acids Res. 2011 Jan;39(Database issue):D152-7 21037258 Cancer Res. 2011 Nov 1;71(21):6738-48 21900400 Science. 2012 Dec 14;338(6113):1465-9 23239736 PLoS One. 2013;8(10). doi:10.1371/annotation/1236c3ed-1497-4917-a083-2f5be4fab835 Animals Chromatin Assembly and Disassembly genetics physiology DNA Methylation genetics Databases, Genetic Epigenesis, Genetic genetics Histones metabolism Humans Male Mice Prostate metabolism Rats PMC3655999 2013 2012 12 25 2013 4 10 2013 5 16 2013 5 23 6 0 2013 5 23 6 0 2013 12 24 6 0 epublish 10.1371/journal.pone.0064289 PONE-D-13-01194 23696878 PMC3655999 23691160 2013 05 21 2013 12 16

1932-6203 8 5 2013 PLoS ONE Cross-contamination of a UROtsa stock with T24 cells--molecular comparison of different cell lines and stocks. e64139 10.1371/journal.pone.0064139 UROtsa is an authentic, immortalized human urothelial cell line that is used to study the effects of metals and other toxic substances, mostly in the context of bladder cancer carcinogenesis. Unusual properties on the molecular level of a provided UROtsa cell line stock prompted us to verify its identity. UROtsa cell line stocks from different sources were tested on several molecular levels and compared with other cell lines. MicroRNA and mRNA expression was determined by Real-Time PCR. Chromosome numbers were checked and PCR of different regions of the large T-antigen was performed. DNA methylation of RARB, PGR, RASSF1, CDH1, FHIT, ESR1, C1QTNF6, PTGS2, SOCS3, MGMT, and LINE1 was analyzed by pyrosequencing and compared with results from the cell lines RT4, T24, HeLa, BEAS-2B, and HepG2. Finally, short tandem repeat (STR) profiling was applied. All tested UROtsa cell line stocks lacked large T-antigen. STR analysis unequivocally identified our main UROtsa stock as the bladder cancer cell line T24, which was different from two authentic UROtsa stocks that served as controls. Analysis of DNA methylation patterns and RNA expression confirmed their differences. Methylation pattern and mRNA expression of the contaminating T24 cell line showed moderate changes even after long-term culture of up to 56 weeks, whereas miRNAs and chromosome numbers varied markedly. It is important to check the identity of cell lines, especially those that are not distributed by major cell banks. However, for some cell lines STR profiles are not available. Therefore, new cell lines should either be submitted to cell banks or at least their STR profile determined and published as part of their initial characterization. Our results should help to improve the identification of UROtsa and other cells on different molecular levels and provide information on the use of urothelial cells for long-term experiments. Johnen Georg G Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, IPA, Bochum, Germany. johnen@ipa-dguv.de Rozynek Peter P von der Gathen Yvonne Y Bryk Oleksandr O Zdrenka Ricarda R Johannes Christian C Weber Daniel G DG Igwilo-Okuefuna O Brien OB Raiko Irina I Hippler Jörg J Brüning Thomas T Dopp Elke E eng Journal Article Research Support, Non-U.S. Gov't 2013 05 17

United States PLoS One 101285081 1932-6203 0 Antigens, Viral, Tumor 0 MicroRNAs 0 RNA, Messenger IM Tohoku J Exp Med. 1978 Apr;124(4):339-49 663932 Cancer Res. 1987 Nov 15;47(22):6066-73 2822239 Proc Natl Acad Sci U S A. 1988 Jul;85(14):5107-11 3293049 Differentiation. 1988 Jun;38(1):60-6 2846394 Proc Natl Acad Sci U S A. 1990 Apr;87(7):2775-9 2181449 Cell. 1990 Aug 10;62(3):503-14 1974172 Urol Res. 1995;23(6):377-80 8788275 Brain Res Dev Brain Res. 1996 Aug 20;95(1):38-43 8873974 Cancer Res. 1999 Apr 15;59(8):1980-6 10213510 Int J Cancer. 1999 Nov 12;83(4):555-63 10508494 In Vitro Cell Dev Biol Anim. 2004 Jul-Aug;40(7):211-5 15638703 Toxicol Appl Pharmacol. 2005 Sep 1;207(2):147-59 16102566 Cancer Genet Cytogenet. 2005 Nov;163(1):17-22 16271951 J Cell Biol. 2005 Dec 5;171(5):835-44 16330712 Nat Rev Genet. 2006 Jan;7(1):21-33 16369569 Oncogene. 2006 Aug 17;25(36):5037-45 16619045 Int J Mol Med. 2006 Oct;18(4):547-57 16964403 Cancer Res. 2007 Sep 15;67(18):8511-8 17875690 Int J Cancer. 2008 Jan 1;122(1):1-4 17960586 Biotechniques. 2007 Nov;43(5):575, 577-8, 581-2 passim 18072586 J Urol. 2009 Jun;181(6):2737-48 19375735 Melanoma Res. 2009 Jun;19(3):146-55 19441164 Kidney Int. 2009 Jun;75(11):1153-65 19340092 Epigenetics. 2009 Apr 1;4(3):176-84 19421002 Cancer Res. 2002 Dec 1;62(23):6973-80 12460915 Int J Cancer. 2003 May 1;104(5):611-6 12594816 Traffic. 2004 Mar;5(3):117-28 15086788 Am J Pathol. 2004 May;164(5):1789-98 15111325 Toxicology. 2008 Jun 27;248(2-3):67-76 18456381 Cancer Res. 2008 Aug 1;68(15):6208-14 18676844 Carcinogenesis. 2008 Aug;29(8):1500-8 18448484 Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2786-94 18843024 Oncol Rep. 2008 Dec;20(6):1419-23 19020723 Toxicology. 2009 Jan 8;255(1-2):107-14 19014992 Hum Exp Toxicol. 2009 Jan;28(1):49-61 19411561 PLoS One. 2009;4(6):e6040 19557180 Clin Cancer Res. 2009 Aug 15;15(16):5060-72 19671845 BMC Cancer. 2009;9:377 19849847 Toxicol Appl Pharmacol. 2009 Dec 1;241(2):221-9 19716837 Int J Cancer. 2010 Jan 1;126(1):302 19856306 Int J Cancer. 2010 Jan 1;126(1):303-4 19859913 Toxicol Sci. 2004 May;79(1):56-63 14976345 Genes Chromosomes Cancer. 2000 Mar;27(3):252-63 10679914 Cancer Res. 2000 Jul 1;60(13):3445-53 10910055 Arch Toxicol. 2000 Aug;74(6):289-99 11005674 Hum Mol Genet. 2001 Jun 15;10(13):1413-9 11440994 Environ Health Perspect. 2001 Aug;109(8):801-8 11564615 Cancer Res. 2001 Dec 15;61(24):8659-63 11751381 Clin Cancer Res. 2002 Feb;8(2):464-70 11839665 Cancer Res. 2002 Feb 15;62(4):961-6 11861364 Int J Cancer. 1973 May;11(3):765-73 4133950 Neoplasma. 1977;24(3):319-26 895941 Toxicol Appl Pharmacol. 2010 Apr 15;244(2):162-73 20045430 PLoS Genet. 2010 Apr;6(4):e1000917 20421991 Int J Cancer. 2010 Jul 1;127(1):1-8 20143388 Biol Reprod. 2010 Jun;82(6):1119-28 20164436 Nat Rev Cancer. 2010 Jun;10(6):441-8 20448633 Cancer Prev Res (Phila). 2010 Jun;3(6):776-86 20501863 Toxicol Sci. 2010 Jul;116(1):44-57 20375083 Cancer Genet Cytogenet. 2010 Dec;203(2):253-62 21156241 J Mol Diagn. 2011 Jan;13(1):29-40 21227392 In Vitro Cell Dev Biol Anim. 2011 Jan;47(1):2-9 21136194 BJU Int. 2011 Feb;107(4):656-63 20735391 Int J Cancer. 2011 Mar 15;128(6):1327-34 20473948 Mol Hum Reprod. 2011 Jun;17(6):344-53 21289002 Mol Biol Rep. 2011 Aug;38(6):4159-70 21116856 BMC Med Genomics. 2011;4:45 21599969 Br J Cancer. 2011 Jul 26;105(3):393-402 21750550 PLoS One. 2011;6(11):e28223 22140553 Toxicology. 2012 Jan 27;291(1-3):102-12 22108045 PLoS One. 2012;7(4):e35363 22530010 Nature. 2012 Sep 6;489(7414):57-74 22955616 Nature. 2012 Dec 13;492(7428):186 23235867 Int J Cancer. 2013 Mar 1;132(5):1232-4 22847338 Am J Pathol. 2002 Oct;161(4):1199-206 12368193 Antigens, Viral, Tumor genetics Cell Line cytology Cell Line, Tumor cytology DNA Contamination DNA Methylation Humans MicroRNAs genetics Microsatellite Repeats genetics RNA, Messenger genetics Real-Time Polymerase Chain Reaction Sequence Analysis, DNA Urothelium cytology PMC3656924 2013 2013 1 30 2013 4 8 2013 5 17 2013 5 22 6 0 2013 5 22 6 0 2013 12 18 6 0 epublish 10.1371/journal.pone.0064139 PONE-D-13-05487 23691160 PMC3656924 23681012 2013 05 17 2013 05 20 2013 07 03

1422-0067 14 5 2013 Int J Mol Sci Methylated DNA and microRNA in Body Fluids as Biomarkers for Cancer Detection. 10307-31 10.3390/ijms140510307 Epigenetic alterations including DNA methylation and microRNAs (miRNAs) play important roles in the initiation and progression of human cancers. As the extensively studied epigenetic changes in tumors, DNA methylation and miRNAs are the most potential epigenetic biomarkers for cancer diagnosis. After the identification of circulating cell-free nuclear acids, increasing evidence demonstrated great potential of cell-free epigenetic biomarkers in the blood or other body fluids for cancer detection. Ma Yanning Y Laboratory of Cancer Biology, Department of Medical Oncology, Institute of Clinical Science, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou 310029, China. jinhc@zju.edu.cn. Wang Xian X Jin Hongchuan H eng Journal Article 2013 05 16

Switzerland Int J Mol Sci 101092791 1422-0067 PMC3676840 2013 3 11 2013 4 01 2013 4 25 2013 5 18 6 0 2013 5 18 6 0 2013 5 18 6 1 epublish ijms140510307 10.3390/ijms140510307 23681012 PMC3676840 23658659 2013 05 09 2013 12 09

1932-6203 8 4 2013 PLoS ONE Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. e62982 10.1371/journal.pone.0062982 Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs. Bozdag Serdar S Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. serdar.bozdag@marquette.edu Li Aiguo A Riddick Gregory G Kotliarov Yuri Y Baysan Mehmet M Iwamoto Fabio M FM Cam Margaret C MC Kotliarova Svetlana S Fine Howard A HA eng Journal Article Research Support, N.I.H., Intramural 2013 04 29

United States PLoS One 101285081 1932-6203 0 Angiogenesis Inhibitors 0 MicroRNAs 0 Polycomb-Group Proteins IM Histol Histopathol. 2000 Jul;15(3):835-42 10963127 Cardiovasc Res. 2012 Feb 1;93(2):232-41 22068159 Lancet. 2002 Mar 23;359(9311):1011-8 11937180 Genes Dev. 2002 Oct 1;16(19):2530-43 12368264 Cancer Res. 2003 Apr 1;63(7):1602-7 12670911 Oncogene. 2003 Apr 17;22(15):2361-73 12700671 Genome Biol. 2003;4(5):P3 12734009 Nat Genet. 2003 Jul;34(3):267-73 12808457 Oncogene. 2003 Jul 31;22(31):4918-23 12894235 Nucleic Acids Res. 2003 Oct 1;31(19):5676-84 14500831 Gerontologist. 1989 Apr;29(2):224-8 2753382 Int J Radiat Oncol Biol Phys. 1993 May 20;26(2):239-44 8387988 Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):793-802 8598355 Cancer Res. 1998 Dec 1;58(23):5489-94 9850084 J Neurooncol. 2004 Nov;70(2):229-43 15674480 Acta Neuropathol. 2005 Jan;109(1):93-108 15685439 Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9 15827123 Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 16199517 Oncol Rep. 2005 Dec;14(6):1583-8 16273260 Cancer Res. 2006 Jan 1;66(1):159-67 16397228 Cancer Cell. 2006 Mar;9(3):157-73 16530701 BMC Cardiovasc Disord. 2006;6:13 16594992 J Clin Oncol. 2006 Aug 20;24(24):3871-9 16921039 Cancer Res. 2006 Oct 1;66(19):9428-36 17018597 Mol Cancer. 2006;5:39 17002787 Cancer Control. 2007 Jan;14(1):44-56 17242670 Trends Genet. 2007 Aug;23(8):413-8 17559965 Mol Cell Biol. 2007 Oct;27(20):7273-83 17709393 Lancet Oncol. 2008 Jan;9(1):29-38 18082451 Nucleic Acids Res. 2008 Jan;36(Database issue):D842-6 17932060 J Clin Oncol. 2008 Jun 20;26(18):3015-24 18565887 Oncogene. 2008 Jun 26;27(28):3999-4007 18278068 Nature. 2008 Oct 23;455(7216):1061-8 18772890 J Clin Oncol. 2009 Feb 10;27(5):740-5 19114704 Cancer Res. 2009 Mar 1;69(5):2091-9 19244127 Neurology. 2009 Apr 7;72(14):1217-22 19349600 Oncologist. 2009 Jun;14(6):621-36 19487335 Nucleic Acids Res. 2009 Jul;37(Web Server issue):W247-52 19487240 Expert Opin Investig Drugs. 2009 Aug;18(8):1061-83 19555299 Nucleic Acids Res. 2010 Jan;38(Database issue):D105-10 19906716 Biochim Biophys Acta. 2010 Feb;1801(2):106-13 19815093 Cancer Cell. 2010 Jan 19;17(1):98-110 20129251 Nature. 2010 Feb 18;463(7283):899-905 20164920 Genome Res. 2010 Apr;20(4):440-6 20219944 Mol Cell Biol. 2010 May;30(9):2120-34 20176809 Cancer Cell. 2010 May 18;17(5):510-22 20399149 PLoS Genet. 2010 May;6(5):e1000952 20485568 J Clin Oncol. 2010 Jun 20;28(18):3061-8 20479398 Neuro Oncol. 2011 Jan;13(1):84-98 20926426 Hum Mol Genet. 2011 Mar 15;20(6):1164-72 21216877 Cancer Res. 2011 Mar 1;71(5):1647-57 21239473 Tumour Biol. 2011 Aug;32(4):677-87 21442281 J Biomed Sci. 2011;18:39 21672207 Blood. 2011 Sep 1;118(9):2622-31 21551235 Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):15231-6 21896759 J Biomed Inform. 2011 Oct;44(5):839-47 21605702 Semin Oncol. 2011 Dec;38 Suppl 4:S2-10 22078644 Oncogene. 2001 Jan 11;20(2):270-5 11313954 Adult Age Factors Aged Aging genetics pathology Angiogenesis Inhibitors therapeutic use Brain Neoplasms blood supply drug therapy genetics mortality DNA Copy Number Variations DNA Methylation Epigenesis, Genetic Exons Female Gene Expression Regulation, Neoplastic Glioblastoma blood supply drug therapy genetics mortality Humans Male MicroRNAs Middle Aged Neovascularization, Pathologic Polycomb-Group Proteins genetics metabolism Polymorphism, Single Nucleotide Survival Analysis PMC3639162 2013 2012 6 12 2013 4 1 2013 4 29 2013 5 10 6 0 2013 5 10 6 0 2013 12 16 6 0 epublish 10.1371/journal.pone.0062982 PONE-D-12-16519 23658659 PMC3639162 23637748 2013 05 02 2013 11 26 2013 12 02

1932-6203 8 4 2013 PLoS ONE MicroRNA-219-2-3p functions as a tumor suppressor in gastric cancer and is regulated by DNA methylation. e60369 10.1371/journal.pone.0060369 Gastric cancer is the most frequent gastrointestinal tumor in adults and is the most lethal form of human cancer. Despite of the improvements in treatments, the underlying mechanism of gastric carcinogenesis is not well known. To define novel modulators that regulate susceptibility to tumorgenesis, we focused on miR-219-2-3p. Quantitative RT-PCR was employed to investigate the level of miR-219-2-3p in gastric cancer (GC) tissues (n = 113) and their matched adjacent normal tissues (n = 113). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate biological effects of miR-219-2-3p. Since silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorgenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-219-2-3p were subsequently examined by quantitative RT-PCR. Finally, the methylation status of CpG island upstream of miR-219-2-3p was analyzed by methylation-specific PCR in GC tissues (n = 22). miR-219-2-3p was down-regulated in GC and cell lines. In addition, the experiments documented the lower expression of miR-219-2-3p in GC specimens with higher grade and later stage tumors. Meanwhile, miR-219-2-3p exerted antiproliferative, proapoptotic, and antimetastatic roles and reduced levels of p-ERK1/2 in GC cells. Furthermore, 5-aza-2'-deoxycytidine and trichostatin A increased the expression (~2 fold) of miR-219-2-3p in GC cells. By methylation-specific PCR, DNA methylation in the upstream region of miR-219-2-3p was detected in both adjacent normal tissues and cancer tissues. As expected, the methylation level was considerably higher in the miR-219-2-3p down-regulated group than up-regulated group. miR-219-2-3p is potentially involved in gastric cancer progression and metastasis by regulating ERK1/2-related signal pathways, which may provide a novel therapeutic strategy for treatment of gastric cancer. Methylation mechanism may be involved in modulating the expression level of miR-219-2-3p in gastric cancer. Lei Huizi H Department of Pathology, Chongqing Medical University, Chongqing, People's Republic of China. Zou Dongling D Li Zheng Z Luo Min M Dong Lei L Wang Bin B Yin Haixin H Ma Yanni Y Liu Changzheng C Wang Fang F Zhang Junwu J Yu Jia J Li Yu Y eng Journal Article Research Support, Non-U.S. Gov't 2013 04 23

United States PLoS One 101285081 1932-6203 0 MIRN219 microRNA, human 0 MicroRNAs IM Science. 2003 Mar 7;299(5612):1540 12624257 PLoS One. 2012;7(7):e41773 22848597 Genes Dev. 2005 Mar 1;19(5):517-29 15741316 Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3788-93 15731348 Ann Med. 2006;38(3):200-11 16720434 Cancer Res. 2006 Aug 1;66(15):7390-4 16885332 Genes Dev. 2006 Aug 15;20(16):2202-7 16882971 J Clin Oncol. 2006 Sep 10;24(26):4309-16 16963731 Oncogene. 2006 Oct 9;25(46):6163-9 17028595 J Biol Chem. 2007 Jan 12;282(2):1479-86 17110380 Cell Cycle. 2007 Jun 15;6(12):1455-9 17581274 Pharmacogenomics J. 2007 Oct;7(5):297-304 17189960 Cancer Res. 2008 Apr 1;68(7):2094-105 18381414 Cancer Res. 2008 Aug 1;68(15):6162-70 18676839 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 J Pathol. 2008 Dec;216(4):471-82 18798223 Clin Cancer Res. 2008 Dec 1;14(23):7843-9 19047113 Science. 2008 Dec 12;322(5908):1695-9 19008416 N Engl J Med. 2008 Dec 18;359(25):2641-50 19092150 Pathol Int. 2009 Mar;59(3):121-36 19261089 Carcinogenesis. 2010 Jan;31(1):27-36 19752007 Int J Cancer. 2010 Sep 1;127(6):1363-72 20073067 Mod Pathol. 2010 Oct;23(10):1404-17 20711171 Acta Neuropathol. 2011 Feb;121(2):193-205 20936480 Nat Med. 2011 Mar;17(3):330-9 21386836 Biochem Biophys Res Commun. 2011 Apr 22;407(4):680-6 21440529 Carcinogenesis. 2011 May;32(5):772-8 21349819 J Clin Oncol. 2011 Aug 1;29(22):3030-6 21709195 J Clin Oncol. 2011 Oct 20;29(30):3968-76 21844504 FEBS Lett. 2012 Mar 23;586(6):884-91 22449976 Neuro Oncol. 2012 May;14(5):596-612 22411914 Ophthalmic Res. 2012;47(4):195-201 22156553 Gastric Cancer. 2012 Jul;15(3):313-22 22179434 Breast Cancer Res. 2010;12(5):R76 20920193 Gastroenterology. 2004 Jan;126(1):382-4 14753224 Adult Aged Aged, 80 and over Base Sequence Cell Line, Tumor Cell Movement genetics Cell Proliferation Cell Survival genetics Computational Biology DNA Methylation Epigenesis, Genetic genetics Female Gene Expression Regulation, Neoplastic genetics Genes, Tumor Suppressor Humans MAP Kinase Signaling System genetics Male MicroRNAs genetics Middle Aged Neoplasm Invasiveness Stomach Neoplasms genetics pathology PMC3634036 2013 2012 12 14 2013 2 26 2013 4 23 2013 5 3 6 0 2013 5 3 6 0 2013 12 16 6 0 epublish 10.1371/journal.pone.0060369 PONE-D-13-00281 23637748 PMC3634036 23617364 2014 1 6

1386-6346 44 1 2014 Jan Hepatol. Res. Alterations of epigenetics and microRNA in hepatocellular carcinoma. 31-42 10.1111/hepr.12147 Studies have shown that alterations of epigenetics and microRNA (miRNA) play critical roles in the initiation and progression of hepatocellular carcinoma (HCC). Epigenetic silencing of tumor suppressor genes in HCC is generally mediated by DNA hypermethylation of CpG island promoters and histone modifications such as histone deacetylation, methylation of histone H3 lysine 9 (H3K9) and tri-methylation of H3K27. Chromatin-modifying drugs such as DNA methylation inhibitors and histone deacetylase inhibitors have shown clinical promise for cancer therapy. miRNA are small non-coding RNA that regulate expression of various target genes. Specific miRNA are aberrantly expressed and play roles as tumor suppressors or oncogenes during hepatocarcinogenesis. We and other groups have demonstrated that important tumor suppressor miRNA are silenced by epigenetic alterations, resulting in activation of target oncogenes in human malignancies including HCC. Restoring the expression of tumor suppressor miRNA by inhibitors of DNA methylation and histone deacetylase may be a promising therapeutic strategy for HCC. © 2013 The Japan Society of Hepatology. Saito Yoshimasa Y Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University, Tokyo, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. Hibino Sana S Saito Hidetsugu H ENG GENBANK ADAM10 ADAM17 JOURNAL ARTICLE 2013 5 26

Hepatol Res 9711801 1386-6346 DNA methylation epigenetics hepatocellular carcinoma histone modification miRNA 2013 3 8 2013 4 12 2013 4 21 2013 5 26 2013 4 27 6 0 2013 4 27 6 0 2013 4 27 6 0 ppublish 23617364 10.1111/hepr.12147 23597195 2013 07 03 2014 01 30

1873-5576 13 5 2013 Jun Curr Cancer Drug Targets Genetic and epigenetic studies for determining molecular targets of natural product anticancer agents. 506-18 Cancer is a disease caused by a series of genetic and epigenetic alterations. Therefore, agents targeting the genetic and/or epigenetic machinery offer potential for the development of anticancer drugs. Accumulating evidence has demonstrated that some common natural products [such as epigallocatechin-3-gallate (EGCG), curcumin, genistein, sulforaphane (SFN) and resveratrol] have anticancer properties through the mechanisms of altering epigenetic processes [including DNA methylation, histone modification, chromatin remodeling, microRNA (miRNA) regulation] and targeting cancer stem cells (CSCs). These bioactive compounds are able to revert epigenetic alterations in a variety of cancers in vitro and in vivo. They exert anticancer effects by targeting various signaling pathways related to the initiation, progression and metastasis of cancer. It appears that natural products hold great promise for cancer prevention and treatment by altering various epigenetic modifications. This review aims to discuss our current understanding of genetic and epigenetic targets of natural products and the effects of some common natural products on cancer chemoprevention and treatment. Wang Yujiong Y Key Laboratory of the Ministry of Education for Conservation and Utilization of Special Biological Resources in Western China, Ningxia 750021, China. Li Yong Y Liu Xiaoming X Cho William C S WC eng Journal Article Research Support, Non-U.S. Gov't Review

Netherlands Curr Cancer Drug Targets 101094211 1568-0096 0 Antineoplastic Agents 0 Biological Products 0 Tumor Markers, Biological IM Animals Antineoplastic Agents therapeutic use Biological Products therapeutic use Epigenomics Gene Expression Profiling Genetic Testing Humans Molecular Targeted Therapy Neoplasms drug therapy genetics Phytotherapy Tumor Markers, Biological antagonists & inhibitors genetics 2012 11 7 2012 11 29 2013 2 3 2013 4 20 6 0 2013 4 20 6 0 2014 1 31 6 0 ppublish CCDT-EPUB-20130417-4 23597195 23589849 2013 05 01 2013 06 27 2013 11 11

1091-6490 110 18 2013 Apr 30 Proc. Natl. Acad. Sci. U.S.A. Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer. 7413-7 10.1073/pnas.1304977110 The optimal management of breast cancer (BC) presents challenges due to the heterogeneous molecular classification of the disease. We performed survival analysis on a cohort of 466 patients with primary invasive ductal carcinoma (IDC), the most frequent type of BC, by integrating mRNA, microRNA (miRNA), and DNA methylation next-generation sequencing data from The Cancer Genome Atlas (TCGA). Expression data from eight other BC cohorts were used for validation. The prognostic value of the resulting miRNA/mRNA signature was compared with that of other prognostic BC signatures. Thirty mRNAs and seven miRNAs were associated with overall survival across different clinical and molecular subclasses of a 466-patient IDC cohort from TCGA. The prognostic RNAs included PIK3CA, one of the two most frequently mutated genes in IDC, and miRNAs such as hsa-miR-328, hsa-miR-484, and hsa-miR-874. The area under the curve of the receiver-operator characteristic for the IDC risk predictor in the TCGA cohort was 0.74 at 60 mo of overall survival (P < 0.001). Most relevant for clinical application, the integrated signature had the highest prognostic value in early stage I and II tumors (receiver-operator characteristic area under the curve = 0.77, P value < 0.001). The genes in the RNA risk predictor had an independent prognostic value compared with the clinical covariates, as shown by multivariate analysis. The integrated RNA signature was successfully validated on eight BC cohorts, comprising a total of 2,399 patients, and it had superior performance for risk stratification with respect to other RNA predictors, including the mRNAs used in MammaPrint and Oncotype DX assays. Volinia Stefano S Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy. stefano.volinia@osumc.edu Croce Carlo M CM eng U01 CA152758 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2013 04 15

United States Proc Natl Acad Sci U S A 7505876 0027-8424 0 MicroRNAs 0 RNA, Messenger IM Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 11553815 Nature. 2012 Jun 21;486(7403):405-9 22722202 Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 12829800 PLoS Biol. 2004 Apr;2(4):E108 15094809 Br J Cancer. 2004 Jul 19;91(2):355-8 15188009 N Engl J Med. 2004 Dec 30;351(27):2817-26 15591335 Lancet. 2005 Feb 19-25;365(9460):671-9 15721472 J Natl Cancer Inst. 2006 Feb 15;98(4):262-72 16478745 Nat Clin Pract Oncol. 2006 Aug;3(8):448-57 16894390 N Engl J Med. 2006 Aug 10;355(6):560-9 16899776 BMC Genomics. 2006;7:278 17074082 N Engl J Med. 2007 Jan 18;356(3):217-26 17229949 Cancer Cell. 2007 Mar;11(3):259-73 17349583 Clin Cancer Res. 2007 Jun 1;13(11):3207-14 17545524 Nature. 2009 Jun 18;459(7249):1005-9 19421193 Stat Med. 2011 Mar 15;30(6):642-53 21337359 JAMA. 2011 May 11;305(18):1873-81 21558518 BMC Cancer. 2011;11:143 21501481 Breast Cancer Res Treat. 2011 Aug;128(3):633-41 20803240 Cancer Res. 2011 Sep 1;71(17):5635-45 21737487 Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3024-9 22315424 Breast Cancer Res. 2011;13(5):R97 21978456 Nature. 2012 Jun 21;486(7403):346-52 22522925 Cell. 2012 Jul 6;150(1):12-27 22770212 Cell. 2012 Aug 17;150(4):842-54 22901813 Nature. 2012 Sep 6;489(7414):57-74 22955616 Nature. 2012 Oct 4;490(7418):61-70 23000897 Clin Cancer Res. 2012 Nov 1;18(21):5972-82 22952344 Cell. 2012 May 25;149(5):979-93 22608084 Nature. 2012 Jun 21;486(7403):395-9 22495314 Nature. 2012 Jun 21;486(7403):400-4 22722201 N Engl J Med. 2002 Dec 19;347(25):1999-2009 12490681 Breast Neoplasms classification genetics pathology Carcinoma, Ductal, Breast genetics pathology Cohort Studies DNA Methylation genetics Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, Neoplasm genetics Genome, Human genetics Humans Kaplan-Meier Estimate MicroRNAs genetics metabolism Neoplasm Invasiveness Prognosis RNA, Messenger genetics metabolism ROC Curve Reproducibility of Results Risk Factors PMC3645522 2013 4 15 2013 4 17 6 0 2013 4 17 6 0 2013 6 29 6 0 ppublish 1304977110 10.1073/pnas.1304977110 23589849 PMC3645522 23549984 2013 04 29 2014 05 22

0219-1032 35 4 2013 Apr Mol. Cells MicroRNA-148a can regulate runt-related transcription factor 3 gene expression via modulation of DNA methyltransferase 1 in gastric cancer. 313-9 10.1007/s10059-013-2314-9 Underexpression of the gene runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to contribute to gastric cancer progression. However, the mechanism underlying aberrant RUNX3 expression has not been fully elucidated. We investigated the role of microRNA-148a (miR-148a) and DNA methyltransferases (DNMTs) in RUNX3 promoter methylation and gene expression. RUNX3 mRNA, RUNX3 protein, and methylation levels were assayed in human gastric cancer tissues and matched normal tissues, and AGS and BGC-823 cells by real-time reverse transcription PCR, Western blot, and methylation-specific PCR, respectively. A correlation between RUNX3 mRNA levels and that of miR-148a was also investigated in gastric cancer tissues. We found that RUNX3 mRNA levels were significantly downregulated in gastric cancer tissues compared with their matched normal tissues, and were closely associated with miR-148a expression. After treatment of human gastric cancer AGS and BGC-823 cells with the DNA methylation inhibitor 5-aza-2'-deoxycytidine, a significant increase in RUNX3 mRNA, RUNX3 protein, and the non-methylated form of the RUNX3 promoter were observed relative to untreated cells. Enforced expression of miR-148a, which can modulate DNMT1 and DNMT3B, also increased the expression of RUNX3 in gastric cancer cells. Knockdown of DNMT1 was associated with increased levels of RUNX3 mRNA and RUNX3 protein, while knockdown of DNMT3B did not have any effect on these in BGC-823 cells. Our results show that miR-148a may regulate RUNX3 expression through modulation of DNMT1-dependent DNA methylation in gastric cancer and highlight a miRNA-epigenetics regulation mechanism of gene expression. Zuo Junbo J Department of General Surgery, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi 214002, China. Xia Jiazeng J Ju Feng F Yan Jiang J Zhu Akao A Jin Shimao S Shan Ting T Zhou Hong H eng Journal Article Research Support, Non-U.S. Gov't 2013 03 29

Korea (South) Mol Cells 9610936 1016-8478 0 Core Binding Factor Alpha 3 Subunit 0 MIRN148 microRNA, human 0 MicroRNAs 0 RNA, Small Interfering 0 Runx3 protein, human EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 EC 2.1.1.37 DNA methyltransferase 3B IM Methods. 2001 Dec;25(4):402-8 11846609 Nature. 2002 Apr 4;416(6880):552-6 11932749 Cell. 2002 Apr 5;109(1):113-24 11955451 Nat Rev Genet. 2002 Jun;3(6):415-28 12042769 Nature. 2012 Feb 16;482(7385):347-55 22337054 Biochem Biophys Res Commun. 2012 Feb 17;418(3):547-52 22290228 Nat Rev Genet. 2012 Jul;13(7):484-92 22641018 Oncogene. 2012 Sep 27;31(39):4302-16 22231444 Med Oncol. 2012 Dec;29(4):2701-9 22167392 Ann Surg Oncol. 2009 Jun;16(6):1686-94 19290488 Blood. 2009 Jun 18;113(25):6411-8 19211935 Lancet. 2009 Aug 8;374(9688):477-90 19625077 Hepatology. 2010 Mar;51(3):881-90 20146264 Eur J Cancer. 2010 May;46(8):1456-63 20176475 J Immunol. 2010 Jun 15;184(12):6773-81 20483747 Oncogene. 2010 Oct 28;29(43):5761-71 20802530 J Cell Biochem. 2011 May;112(5):1243-9 21465522 Arthritis Rheum. 2011 May;63(5):1376-86 21538319 EMBO Rep. 2011 Jul;12(7):647-56 21660058 Int J Cancer. 2011 Oct 1;129(7):1586-98 21128246 BMC Gastroenterol. 2011;11:92 21867527 Oncogene. 2012 Jan 26;31(4):527-34 21706051 PLoS One. 2012;7(1):e30635 22295098 Cell. 1999 Oct 29;99(3):247-57 10555141 Bioessays. 2003 Nov;25(11):1071-84 14579248 Am J Pathol. 2004 Feb;164(2):689-99 14742272 Lab Invest. 2004 Apr;84(4):479-84 14968123 Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11797-801 7527544 Cancer Sci. 2005 Apr;96(4):227-31 15819721 Cancer Res. 2005 Sep 1;65(17):7743-50 16140942 Cancer Res. 2005 Oct 15;65(20):9347-54 16230397 Cancer. 2006 Feb 1;106(3):483-93 16362978 J Mol Med (Berl). 2007 Oct;85(10):1137-48 17571247 Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15805-10 17890317 RNA. 2008 May;14(5):872-7 18367714 Clin Cancer Res. 2009 May 1;15(9):2988-94 19336521 Cell Line, Tumor Core Binding Factor Alpha 3 Subunit biosynthesis genetics metabolism CpG Islands DNA (Cytosine-5-)-Methyltransferase metabolism DNA Methylation Down-Regulation Gene Expression Regulation, Neoplastic Humans MicroRNAs biosynthesis genetics metabolism Plasmids administration & dosage genetics RNA, Small Interfering administration & dosage genetics Stomach Neoplasms genetics metabolism pathology Transfection PMC3887893 2012 12 3 2013 2 12 2013 2 5 2013 3 29 2013 4 4 6 0 2013 4 4 6 0 2014 5 23 6 0 ppublish 10.1007/s10059-013-2314-9 23549984 PMC3887893 23508887 2013 10 30 2014 06 07

1559-0283 67 2 2013 Nov Cell Biochem. Biophys. DNA methylation and cancer development: molecular mechanism. 501-13 10.1007/s12013-013-9555-2 DNA methylation is a significant regulator of gene expression, and its role in carcinogenesis recently has been a subject of remarkable interest. The aim of this review is to analyze the mechanism and cell regulatory effects of both hypo- and hyper-DNA methylation on cancer. In this review, we report new developments and their implications regarding the effects of DNA methylation on cancer development. Indeed, alteration of the pattern of DNA methylation has been a constant finding in cancer cells of the same type and differences in the pattern of DNA methylation not only occur in a variety of tumor types, but also in developmental processes Furthermore, the pattern of histone modification appears to be a predicator of the risk of recurrence of human cancers. It is well known that hypermethylation represses transcription of the promoter sections of tumor-suppressor genes leading to gene silencing. However, hypomethylation also has been identified as a cause of oncogenesis. Furthermore, experiments concerning the mechanism of methylation and its control have led to the discovery of many regulatory enzymes and proteins. This review reports on methods developed for the detection of 5-hydroxymethylcytosine methylation at the 5-methylcytosine of protein domains in the CpG context compared to non-methylated DNA, histone modification, and microRNA change. Akhavan-Niaki Haleh H Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran. Samadani Ali Akbar AA eng Journal Article Review

United States Cell Biochem Biophys 9701934 1085-9195 0 Histones 935E97BOY8 Folic Acid IM Animals Carcinogenesis DNA Methylation Folic Acid metabolism Histones metabolism Humans Mutation Neoplasms genetics metabolism pathology 2013 3 20 6 0 2013 3 20 6 0 2014 6 8 6 0 ppublish 10.1007/s12013-013-9555-2 23508887 23487440 2013 04 30 2013 06 17

1465-3621 43 5 2013 May Jpn. J. Clin. Oncol. MicroRNAs in Cancer: the 22nd Hiroshima Cancer Seminar/the 4th Japanese Association for RNA Interference Joint International Symposium, 30 August 2012, Grand Prince Hotel Hiroshima. 579-82 10.1093/jjco/hyt037 The joint international symposium of the 22nd Hiroshima Cancer Seminar and the 4th Japanese Association for RNA Interference focused on a pivotal role of microRNAs in carcinogenesis, progression and therapy of human cancer. Mammalian immune regulator MCPIP1 (Zc3h12a) RNase acts as a novel suppressor of microRNA activity and biogenesis, suggesting the involvement of MCPIP1 in the alteration of microRNA biogenesis in tumorigenesis. Gene set enrichment analysis and functional assignment of microRNAs via enrichment analysis enable the prediction of microRNA activities from mRNA expression data by combining rank-based enrichment analysis and weighted evaluation of microRNA-mRNA interactions. MiR-124 and miR-203 function as tumor-suppressor microRNAs silenced by DNA methylation in hepatocellular carcinoma. Stella-induced DNA hypomethylation would confer the pathogenic function of DNA hypomethylation in cancer. Senescence-associated microRNA, miR-22, suppresses tumor growth and metastasis in vivo in a murine breast cancer model, and exosomal senescence-associated microRNA may affect the tumor microenvironment. The therapeutic potential of microRNAs for preventing and treating lung cancer using the Kras(LSL-G12D/+);p53(LSL-R172H/+)mouse model suggests that miR-34 may be useful in sensitizing tumors to other conventional therapeutics. MiR-1 and miR-133a cluster may function as tumor suppressors regulating novel pathways in human cancers. The down-regulation of miR-148a is implicated in invasion of gastric cancer, while high miR-21 expression in colorectal cancer is associated with poor survival. Neutral sphingomyelinase 2 regulates exosomal microRNA secretion and promotes angiogenesis within the tumor microenvironment as well as metastasis; in particular, the exosomal miR-210 secretion by neutral sphingomyelinase 2 confers the formation of the tumor vessel network. Tahara Hidetoshi H Department of Cellular and Molecular Biology, Hiroshima University Graduate School of Biomedical Science, Hiroshima, Japan. Kay Mark A MA Yasui Wataru W Tahara Eiichi E eng Congresses 2013 03 13

England Jpn J Clin Oncol 0313225 0368-2811 0 MIRN1 microRNA, human 0 MIRN124 microRNA, human 0 MIRN133 microRNA, human 0 MIRN148 microRNA, human 0 MIRN203 microRNA, human 0 MIRN210 microRNA, human 0 MIRN34 microRNA, human 0 MicroRNAs 0 Transcription Factors 0 ZC3H12A protein, human EC 3.1.- Ribonucleases IM Animals Breast Neoplasms genetics metabolism DNA Methylation Disease Progression Female Genes, Tumor Suppressor Humans Japan Liver Neoplasms genetics metabolism Lung Neoplasms prevention & control therapy MicroRNAs metabolism Neoplasms genetics metabolism Neoplasms, Experimental genetics metabolism Neovascularization, Pathologic metabolism RNA Interference Ribonucleases metabolism Transcription Factors metabolism 2013 3 13 2013 3 15 6 0 2013 3 15 6 0 2013 6 19 6 0 ppublish hyt037 10.1093/jjco/hyt037 23487440 23474752 2014 03 06 2014 04 29

1476-5594 33 10 2014 Mar 6 Oncogene Loss of the polycomb protein Mel-18 enhances the epithelial-mesenchymal transition by ZEB1 and ZEB2 expression through the downregulation of miR-205 in breast cancer. 1325-35 10.1038/onc.2013.53 The epithelial-mesenchymal transition (EMT) is the pivotal mechanism underlying the initiation of cancer invasion and metastasis. Although Mel-18 has been implicated in several biological processes in cancer, its function in the EMT of human cancers has not yet been studied. Here, we demonstrate that Mel-18 negatively regulates the EMT by epigenetically modulating miR-205. We identified miR-205 as a novel target of Mel-18 using a microRNA microarray analysis and found that Mel-18 increased miR-205 transcription by the inhibition of DNA methyltransferase-mediated DNA methylation of the miR-205 promoter, thereby downregulating its target genes, ZEB1 and ZEB2. Furthermore, the loss of Mel-18 promoted ZEB1- and ZEB2-mediated downregulation of E-cadherin transcription and also enhanced the expression of mesenchymal markers, leading to increased migration and invasion in MCF-7 cells. In MDA-MB-231 cells, Mel-18 overexpression restored E-cadherin expression, resulting in reduced migration and invasion. These effects were reversed by miR-205 overexpression or inhibition. A tumor xenograft with Mel-18 knockdown MCF-7 cells consistently showed increased ZEB1 and ZEB2 expression and decreased E-cadherin expression. Taken together, these results suggest that Mel-18 functions as a tumor suppressor by its novel negative control of the EMT, achieved through regulating the expression of miR-205 and its target genes, ZEB1 and ZEB2. Lee J-Y JY Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea. Park M K MK College of Pharmacy, Dongguk University, Seoul, Korea. Park J-H JH Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea. Lee H J HJ College of Pharmacy, Dongguk University, Seoul, Korea. Shin D H DH Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea. Kang Y Y Department of Molecular Biology, Princeton University, Princeton, NJ, USA. Lee C H CH College of Pharmacy, Dongguk University, Seoul, Korea. Kong G G 1] Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, Korea [2] Department of Pathology, College of Medicine, Hanyang University, Seoul, Korea. eng Journal Article Research Support, Non-U.S. Gov't 2013 03 11

England Oncogene 8711562 0950-9232 0 CDH1 protein, human 0 Cadherins 0 Homeodomain Proteins 0 MIRN205 microRNA, human 0 MicroRNAs 0 PCGF2 protein, human 0 Repressor Proteins 0 Transcription Factors 0 ZEB1 protein, human 0 ZEB2 protein, human EC 6.3.2.19 Polycomb Repressive Complex 1 IM Animals Breast Neoplasms genetics metabolism pathology Cadherins genetics metabolism DNA Methylation Down-Regulation Epigenesis, Genetic Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Homeodomain Proteins genetics metabolism Humans MCF-7 Cells Mice Mice, Inbred NOD Mice, SCID MicroRNAs genetics metabolism Neoplasm Transplantation Polycomb Repressive Complex 1 physiology Repressor Proteins genetics metabolism Transcription Factors genetics metabolism 2012 8 22 2012 12 30 2013 1 21 2013 3 11 2013 3 12 6 0 2013 3 12 6 0 2014 4 30 6 0 ppublish onc201353 10.1038/onc.2013.53 23474752 23436656 2013 04 22 2013 06 13 2014 04 22

1083-351X 288 16 2013 Apr 19 J. Biol. Chem. The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2). 10973-85 10.1074/jbc.M112.434340 MicroRNAs are involved in regulating the biology of cancer cells, but their involvement in chemoresistance is not fully understood. We found that miR-663 was up-regulated in our induced multidrug-resistant MDA-MB-231/ADM cell line and that this up-regulation was closely related to chemosensitivity. In the present study, we aimed to clarify the role of miR-663 in regulating the chemoresistance of breast cancer. MicroRNA microarray and quantitative RT-PCR assays were used to identify differentially expressed microRNAs. Cell apoptosis was evaluated by annexin V/propidium iodide staining, TUNEL, and reactive oxygen species generation analysis. The expression of miR-663 and HSPG2 in breast cancer tissues was detected by in situ hybridization and immunohistochemistry. The potential targets of miR-663 were defined by a luciferase reporter assay. Bisulfite sequencing PCR was used to analyze the methylation status. We found that miR-663 was significantly elevated in MDA-MB-231/ADM cells, and the down-regulation of miR-663 sensitized MDA-MB-231/ADM cells to both cyclophosphamide and docetaxel. The overexpression of miR-663 in breast tumor tissues was associated with chemoresistance; in MDA-MB-231 cells, this chemoresistance was accompanied by the down-regulation of HSPG2, which was identified as a target of miR-663. MDA-MB-231/ADM contained fewer methylated CpG sites than its parental cell line, and miR-663 expression in MDA-MB-231 cells was reactivated by 5-aza-29-deoxycytidine treatment, indicating that DNA methylation may play a functional role in the expression of miR-663. Our findings suggest that the overexpression of hypomethylated miR-663 induced chemoresistance in breast cancer cells by down-regulating HSPG2, thus providing a potential target for the development of an microRNA-based approach for breast cancer therapy. Hu Haiyan H Breast Tumor Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, 107 Yanjiang West Road, Guangzhou 510120, China. Li Shuqin S Cui Xiuying X Lv Xiaobin X Jiao Yu Y Yu Fengyan F Yao Herui H Song Erwei E Chen Yongsong Y Wang Minghui M Lin Ling L eng Journal Article Research Support, Non-U.S. Gov't 2013 02 22

United States J Biol Chem 2985121R 0021-9258 0 Antimetabolites, Antineoplastic 0 Antineoplastic Agents, Alkylating 0 DNA, Neoplasm 0 Heparan Sulfate Proteoglycans 0 MIRN633 microRNA, human 0 MicroRNAs 0 Neoplasm Proteins 0 RNA, Neoplasm 0 Taxoids 143972-95-6 perlecan 15H5577CQD docetaxel 776B62CQ27 decitabine 8N3DW7272P Cyclophosphamide M801H13NRU Azacitidine IM Eur J Cancer. 2010 Jan;46(2):298-311 19948396 J Biol Chem. 2012 Oct 12;287(42):34970-8 22927443 Breast Cancer Res. 2010;12(2):201 20346098 J Pharmacol Sci. 2010;114(3):276-80 20953119 Eur J Cancer. 2010 Dec;46(18):3158-68 20932740 J Biol Chem. 2010 Dec 17;285(51):39759-67 20870728 Clin Chem. 2011 Jan;57(1):18-32 21059829 J Biol Chem. 2011 Feb 4;286(5):3741-54 21068389 Cancer Cell. 2011 Apr 12;19(4):541-55 21481794 FEBS J. 2011 May;278(10):1598-609 21395977 Clin Cancer Res. 2011 Nov 15;17(22):7105-15 21953503 J Biol Chem. 2012 Jan 20;287(4):2907-14 22147694 Gene Expr. 2011;15(3):141-51 22268296 J Biol Chem. 2012 Feb 17;287(8):5639-49 22117060 J Biol Chem. 2012 Feb 17;287(8):5267-77 22174421 J Natl Cancer Inst. 2012 Apr 4;104(7):528-40 22395642 Pharmacogenomics. 2012 Apr;13(6):709-19 22515613 J Biol Chem. 2012 May 18;287(21):17065-76 22457358 Breast. 2012 Jun;21(3):343-9 22425607 Oncogene. 2012 Oct 11;31(41):4421-33 22249270 Nature. 2005 Jun 9;435(7043):834-8 15944708 Cell. 2007 Jun 29;129(7):1401-14 17604727 J Clin Oncol. 2009 Jun 10;27(17):2809-15 19380452 Oncol Rep. 2010 Jul;24(1):105-12 20514450 Antimetabolites, Antineoplastic pharmacology Antineoplastic Agents, Alkylating pharmacology Apoptosis drug effects genetics Azacitidine analogs & derivatives pharmacology Breast Neoplasms drug therapy genetics metabolism pathology Cell Line, Tumor Cyclophosphamide pharmacology DNA Methylation drug effects genetics DNA, Neoplasm genetics metabolism Down-Regulation drug effects genetics Drug Resistance, Neoplasm Female Gene Expression Regulation, Neoplastic Heparan Sulfate Proteoglycans biosynthesis genetics Humans Methylation MicroRNAs biosynthesis genetics Neoplasm Proteins biosynthesis genetics RNA, Neoplasm biosynthesis genetics Taxoids pharmacology PMC3630848 2013 2 22 2013 2 26 6 0 2013 2 26 6 0 2013 6 14 6 0 ppublish M112.434340 10.1074/jbc.M112.434340 23436656 PMC3630848 23426183 2013 03 04 2013 05 13 2013 11 13

1558-8238 123 3 2013 Mar 1 J. Clin. Invest. Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis. 1241-61 10.1172/JCI61271 61271 MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxy-azacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy. Xi Sichuan S Thoracic Oncology Section, Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892, USA. Xu Hong H Shan Jigui J Tao Yongguang Y Hong Julie A JA Inchauste Suzanne S Zhang Mary M Kunst Tricia F TF Mercedes Leandro L Schrump David S DS eng ZIA BC 011122 BC NCI NIH HHS United States ZIA BC 011418 BC NCI NIH HHS United States Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't 2013 02 15

United States J Clin Invest 7802877 0021-9738 0 BMI1 protein, human 0 HNF1A protein, human 0 Hepatocyte Nuclear Factor 1-alpha 0 Histones 0 KRAS protein, human 0 MIRN487 microRNA, human 0 MYC protein, human 0 MicroRNAs 0 Proto-Oncogene Proteins 0 Proto-Oncogene Proteins c-myc 0 SUZ12 protein, human 0 Smoke 0 Transforming Growth Factor beta1 0 WNT5A protein, human 0 Wnt Proteins 0 histone H2A.F-Z EC 2.1.1.43 Polycomb Repressive Complex 2 EC 3.6.5.2 ras Proteins EC 6.3.2.19 Polycomb Repressive Complex 1 AIM IM Biochim Biophys Acta. 2012 Nov;1822(11):1692-704 22885155 Cell. 2012 Sep 14;150(6):1121-34 22980976 Ann N Y Acad Sci. 2012 Oct;1271:118-28 23050973 Cell Cycle. 2012 Oct 1;11(19):3543-9 22895111 Carcinogenesis. 2011 Nov;32(11):1597-606 21828057 Nucleic Acids Res. 2011 Nov;39(21):9345-56 21821656 Mol Oncol. 2012 Dec;6(6):590-610 23102669 Genome Res. 2012 Dec;22(12):2497-506 22960375 Biochim Biophys Acta. 2013 Feb;1830(2):2385-94 23104383 Mol Aspects Med. 2013 Jul-Aug;34(4):863-74 22771542 Br J Cancer. 2011 Oct 25;105(9):1352-61 21970883 Epigenomics. 2011 Feb;3(1):83-92 22126155 Acta Physiol (Oxf). 2012 Jan;204(1):17-33 21518267 Clin Cancer Res. 2012 Jan 1;18(1):77-90 22028491 EMBO Mol Med. 2012 Mar;4(3):143-59 22351564 Genome Res. 2012 May;22(5):837-49 22391556 Mol Cancer Ther. 2012 May;11(5):1203-13 22411898 Antioxid Redox Signal. 2012 Jul 15;17(2):205-23 22044221 Cancer. 2001 Mar 1;91(5):964-71 11251948 Cancer Genet Cytogenet. 2002 Jun;135(2):177-81 12127403 Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10143-8 15210990 J Clin Oncol. 2005 Dec 1;23(34):8765-73 16314637 Genes Dev. 2006 Mar 15;20(6):711-22 16543223 Clin Cancer Res. 2006 Oct 1;12(19):5777-85 17020984 Am J Physiol Lung Cell Mol Physiol. 2007 May;292(5):L1248-56 17220372 Cell. 2007 May 18;129(4):823-37 17512414 Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14366-71 17726103 PLoS One. 2008;3(5):e2125 18461184 J Clin Oncol. 2008 Jun 10;26(17):2846-53 18539963 Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11857-62 18697930 Cell. 2008 Nov 14;135(4):649-61 18992931 Genes Dev. 2008 Nov 15;22(22):3172-83 19056895 Cancer Res. 2009 Apr 15;69(8):3570-8 19351856 Clin Transl Oncol. 2009 Jul;11(7):411-27 19574199 Nature. 2009 Jul 23;460(7254):479-86 19536157 Swiss Med Wkly. 2009 Oct 3;139(39-40):554-63 19838873 Stem Cells. 2009 Nov;27(11):2691-702 19650037 Am J Respir Cell Mol Biol. 2010 Jan;42(1):21-31 19329555 Carcinogenesis. 2010 Jan;31(1):100-10 19934210 Cancer. 2010 Feb 1;116(3):670-5 20029977 Cancer Res. 2010 Feb 1;70(3):968-78 20086175 PLoS One. 2010;5(2):e9163 20161795 J Thorac Oncol. 2010 Apr;5(4):521-5 20130485 J Clin Invest. 2010 Apr;120(4):1298-309 20237410 Oncogene. 2010 Jun 24;29(25):3650-64 20440268 PLoS Biol. 2010;8(7):e1000414 20625544 Nature. 2010 Jul 15;466(7304):388-92 20512117 Expert Rev Anticancer Ther. 2010 Oct;10(10):1569-75 20942628 Trends Genet. 2010 Nov;26(11):476-83 20832136 J Exp Med. 2010 Oct 25;207(11):2287-95 20975044 PLoS One. 2010;5(10):e13764 21048943 Dev Cell. 2010 Nov 16;19(5):651-61 21074716 Cancer Res. 2011 Mar 15;71(6):2212-21 21406400 Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5626-31 21427231 Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6205-10 21444826 Cancer Res. 2011 Apr 15;71(8):3087-97 21363915 Mol Biol Cell. 2011 May 15;22(10):1686-98 21411626 Biochem Biophys Res Commun. 2011 Jun 3;409(2):222-8 21554857 BMC Genomics. 2011;12:329 21702984 Mol Cell Biochem. 2011 Sep;355(1-2):309-14 21695462 Oncogene. 2011 Aug 4;30(31):3404-15 21383689 PLoS One. 2011;6(9):e25168 21980391 Clin Chem Lab Med. 2011 Oct;49(10):1591-603 21767219 Cancer J. 2012 May-Jun;18(3):268-74 22647364 Trends Pharmacol Sci. 2012 Jul;33(7):382-93 22613783 DNA Cell Biol. 2012 Aug;31(8):1358-64 22662865 Cancer Res. 2012 Aug 15;72(16):4178-92 22751465 J Clin Invest. 2012 Sep 4;122(9):3170-83 22850877 Adenocarcinoma etiology genetics metabolism secondary Animals Base Sequence Binding Sites Cell Aging Cell Line, Tumor Cell Transformation, Neoplastic genetics metabolism Chromatin Assembly and Disassembly CpG Islands DNA Methylation Epigenesis, Genetic Female Gene Expression Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor Hepatocyte Nuclear Factor 1-alpha metabolism physiology Histones metabolism Humans Lung Neoplasms etiology genetics metabolism pathology Male Mice Mice, Nude MicroRNAs genetics metabolism Middle Aged Neoplasm Transplantation Polycomb Repressive Complex 1 genetics metabolism Polycomb Repressive Complex 2 genetics metabolism Proto-Oncogene Proteins genetics metabolism Proto-Oncogene Proteins c-myc genetics metabolism RNA Interference Smoke adverse effects Smoking adverse effects Tobacco chemistry Transforming Growth Factor beta1 physiology Wnt Proteins genetics metabolism ras Proteins genetics metabolism PMC3582115 2011 10 4 2013 1 3 2013 2 15 2013 2 15 2013 2 22 6 0 2013 2 22 6 0 2013 5 15 6 0 ppublish 61271 10.1172/JCI61271 23426183 PMC3582115 23369492 2013 02 01 2013 08 12 2013 11 13

1755-8794 6 Suppl 1 2013 BMC Med Genomics Breast cancer subtyping from plasma proteins. S6 10.1186/1755-8794-6-S1-S6 Early detection of breast cancer in blood is both appealing clinically and challenging technically due to the disease's illusive nature and heterogeneity. Today, even though major breast cancer subtypes have been characterized, i.e., luminal A, luminal B, HER2+, and basal-like, little is known about the heterogeneity of breast cancer in blood, which could help to discover minimally invasive protein biomarkers with which clinical researchers can detect, classify, and monitor different breast cancer subtypes. In this study, we performed an integrative pathway-assisted clustering analysis of breast cancer subtypes from plasma proteome samples collected from 80 patients diagnosed with breast cancer and 80 healthy women. First, four breast cancer subtypes and additionally unknown subtype (according to existing annotation) were determined based on pathology lab test results in primary tumors of enrolled patients. Next, we developed and applied four distance metrics, i.e., Protein Intensity, Q-Value, Pathway Profile, and Distance Score Function, to measure and characterize these cancer subtypes. Then, we developed a permutation test to evaluate the significant protein level changes in each biological pathway for each breast cancer subtype, using q-value. Lastly, we developed a pathway-protein matrix for each of the four distance methods to estimate the distance between breast cancer subtypes, for which further Pathway Association Network analysis were performed. We found that 1) the luminal group (luminal A and luminal B) are clustered together, as well as the basal group (basal-like and HER2+) and 2) luminal A and luminal B are more close to each other than basal-like and HER2+ to each other. Our results were consistent with a recent independent breast cancer research from the Cancer Genome Atlas Network using genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our results showed that changes of different breast cancer subtypes at the pathway level are more profound and less variable than those at the molecular level. Similar subtypes share distinct yet similar pathway activation networks, while dissimilar subtypes are different also at the level of pathway activation networks. The results also showed that distance or similarity of cancer subtypes based on pathway analysis might be able to provide further insight into the intrinsic relationship of breast cancer subtypes. We believe integrative pathway-assisted proteomics analysis described here can become a model for reliable clustering or classification of other cancer subtypes. Zhang Fan F Department of Academic and Institutional Resources and Technology, University of North Texas Health Science Center, Fort Worth 76107, USA. Chen Jake Y JY eng U24CA126480-01 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2013 01 23

England BMC Med Genomics 101319628 1755-8794 0 Biological Markers 0 Blood Proteins 0 Proteome IM PLoS Genet. 2008 Apr;4(4):e1000054 18437204 BMC Bioinformatics. 2012;13 Suppl 15:S7 23046449 Brief Funct Genomic Proteomic. 2008 Sep;7(5):329-39 18579615 Clin Exp Metastasis. 2009;26(3):205-13 19112599 Mol Oncol. 2007 Sep;1(2):172-80 19383293 Cancer Genomics Proteomics. 2009 May-Jun;6(3):141-7 19487543 Oncogene. 2000 Feb 21;19(8):1085-91 10713694 Nature. 2000 Aug 17;406(6797):747-52 10963602 Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 11553815 Nature. 2002 Jan 31;415(6871):530-6 11823860 Clin Chem. 2002 Aug;48(8):1296-304 12142387 Cell. 2003 Jun 27;113(7):821-3 12837240 Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 12829800 Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5 12883005 Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10393-8 12917485 Cancer Res. 1989 May 15;49(10):2766-72 2713860 Am J Pathol. 1992 May;140(5):1039-43 1374587 Lancet. 2005 Feb 19-25;365(9460):671-9 15721472 Cancer Res. 2005 Mar 15;65(6):2170-8 15781628 J Proteome Res. 2005 Jul-Aug;4(4):1442-50 16083298 Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11651-6 16087863 JAMA. 2006 Jun 7;295(21):2492-502 16757721 Proc Natl Acad Sci U S A. 2007 May 22;104(21):8685-90 17502601 Cancer Genet Cytogenet. 2007 Jul 15;176(2):107-14 17656252 J Clin Invest. 2007 Nov;117(11):3155-63 17975657 Brief Bioinform. 2007 Sep;8(5):333-46 17638813 Breast Cancer Res Treat. 2008 Mar;108(2):183-90 17468948 Cancer Genomics Proteomics. 2009 May-Jun;6(3):177-82 19487546 Clin Med Res. 2009 Jun;7(1-2):4-13 19574486 OMICS. 2009 Aug;13(4):291-300 19624269 BMC Bioinformatics. 2009;10 Suppl 11:S5 19811689 BMC Genomics. 2010;11 Suppl 2:S12 21047379 Cancer Discov. 2012 Feb;2(2):172-89 22585861 Breast Cancer Res. 2010;12(5):R68 20813035 J Mammary Gland Biol Neoplasia. 2008 Jun;13(2):259-68 18454307 Adult Algorithms Biological Markers blood Blood Proteins genetics metabolism Breast Neoplasms blood classification pathology Cluster Analysis Female Humans Middle Aged Neoplasm Grading Oligonucleotide Array Sequence Analysis Proteome metabolism Proteomics PMC3552699 2013 1 23 2013 2 2 6 0 2013 2 13 6 0 2013 8 13 6 0 ppublish 1755-8794-6-S1-S6 10.1186/1755-8794-6-S1-S6 23369492 PMC3552699 23380243 2013 05 13 2013 07 12 2013 11 21

1879-3185 307 2013 May 10 Toxicology Epigenetics and pesticides. 35-41 10.1016/j.tox.2013.01.017 S0300-483X(13)00022-X Pesticides, a wide class of environmental contaminants, may cause both acute and delayed health effects in exposed subjects. These effects can range from simple irritation of the skin and eyes to more severe effects such as affecting the nervous system, the reproductive system and cancer. The molecular mechanisms underlying such effects are still under investigation. Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications and microRNA expression, can be triggered by environmental factors. We review current evidences indicating that epigenetic modifications may mediate pesticide effects on human health. In vitro, animal, and human investigations have identified several classes of pesticides that modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides and insecticides. Several investigations have examined the effects of environmental exposures and epigenetic markers, and identified toxicants that modify epigenetic states. These modifications are similar to the ones found in pathological tissue samples. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticides health effects, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved. Collotta M M Center of Molecular and Genetic Epidemiology, Department of Clinical Sciences and Community Health, Università degli Studi di Milano and Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Via San Barnaba 8, Milan 20122, Italy. Bertazzi P A PA Bollati V V eng Journal Article Research Support, Non-U.S. Gov't Review 2013 02 01

Ireland Toxicology 0361055 0300-483X 0 Endocrine Disruptors 0 Histones 0 MicroRNAs 0 Pesticides N712M78A8G Arsenic IM Animals Arsenic adverse effects DNA Methylation drug effects Endocrine Disruptors adverse effects Environmental Exposure adverse effects Epigenesis, Genetic drug effects Epigenomics Histones drug effects Humans Lymphoma, Non-Hodgkin chemically induced MicroRNAs drug effects Pesticides adverse effects 2012 6 14 2013 1 8 2013 1 16 2013 2 1 2013 2 6 6 0 2013 2 6 6 0 2013 7 16 6 0 ppublish S0300-483X(13)00022-X 10.1016/j.tox.2013.01.017 23380243 23316035 2013 01 18 2013 03 26

1538-7445 73 2 2013 Jan 15 Cancer Res. Genome-wide epigenetic regulation of miRNAs in cancer. 473-7 10.1158/0008-5472.CAN-12-3731 Aberrant microRNA (miRNA) expression contributes to tumorigenesis and cancer progression. Although the number of reported deregulated miRNAs in various cancer types is growing fast, the underlying mechanisms of aberrant miRNA regulation are still poorly studied. Epigenetic alterations including aberrant DNA methylation deregulate miRNA expression, which was first shown by reexpression of miRNAs upon pharmacologic DNA demethylation. However, studying the influence of DNA methylation on miRNA transcription on a genome-wide level was hampered by poor miRNA promoter annotation. Putative miRNA promoters were identified on a genome-wide level by using common promoter surrogate markers (e.g., histone modifications) and were later validated as such in different tumor entities. Integrating promoter datasets and global DNA methylation analysis revealed an extensive influence of DNA hyper- as well as hypomethylation on miRNA regulation. In this review, we summarize the current knowledge of the field and discuss recent efforts to map miRNA promoter sequences and to determine the contribution of epigenetic mechanisms to the regulation of miRNA expression. We discuss examples of tumor suppressive and oncogenic miRNAs such as the miR-34 and miR-21 family, respectively, which highlight the complexity and consequences of epigenetic miRNA deregulation. Baer Constance C Department of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany. Claus Rainer R Plass Christoph C eng Journal Article Research Support, Non-U.S. Gov't Review 2013 01 10

United States Cancer Res 2984705R 0008-5472 0 MicroRNAs IM DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans MicroRNAs physiology Promoter Regions, Genetic 2013 1 10 2013 1 15 6 0 2013 1 15 6 0 2013 3 27 6 0 ppublish 0008-5472.CAN-12-3731 10.1158/0008-5472.CAN-12-3731 23316035 23238276 2013 10 21 2013 12 10

1879-3185 313 1 2013 Nov 8 Toxicology Epigenetic effects of nano-sized materials. 3-14 10.1016/j.tox.2012.12.002 S0300-483X(12)00421-0 The term epigenetics includes several phenomena such as DNA methylation, histone tail modifications, and microRNA mediated mechanisms, which are able to mold the chromatin structure and/or gene expression levels, without altering the primary DNA sequence. Environmental agents can exert epigenetic properties and there is increasing evidence of epigenetic deregulation of gene expression in several human diseases, including cancer, cardiovascular diseases, autism spectrum disorders, autoimmune diseases, and neurodegeneration, among others. Given the widespread use and dispersion in the environment of nano-sized materials, this article summarizes the studies performed so far to evaluate their potential epigenetic properties. Those studies highlight the ability of certain nano-sized compounds to induce an impaired expression of genes involved in DNA methylation reactions leading to global DNA methylation changes, as well as changes of gene specific methylation of tumor suppressor genes, inflammatory genes, and DNA repair genes, all potentially involved in cancer development. Moreover, some nano-sized compounds are able to induce changes in the acetylation and methylation of histone tails, as well as microRNA deregulated expression. We also provided a detailed description of currently available methodologies to evaluate epigenetic modifications. Standard protocols are currently available to evaluate cytotoxic and genotoxic effects of nano-sized materials. By contrast, there are at present no available standard protocols to evaluate the epigenetic potential of any given compound. The currently available methodologies offer different, but often complementary information to characterize potential epigenetic changes induced by exposure to nano-sized compounds. Given the widespread use and dispersion in the environment of nano-sized materials, at present and foreseeable in the near future, and in light of the indication of potential epigenetic properties here reviewed, more attention should be paid to unravel the consequences of such effects in future studies. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved. Stoccoro Andrea A Department of Translational Research and New Technologies in Medicine and Surgery, Medical Genetics Laboratory, University of Pisa, Pisa, Italy. Karlsson Hanna L HL Coppedè Fabio F Migliore Lucia L eng Journal Article Research Support, Non-U.S. Gov't Review 2012 12 10

Ireland Toxicology 0361055 0300-483X 0 Histones 0 MicroRNAs IM Animals DNA Methylation drug effects Epigenesis, Genetic drug effects Gene Expression Regulation drug effects Histones genetics metabolism Humans MicroRNAs genetics Nanoparticles toxicity Particle Size DNA methylation Epigenetics Histone modifications MicroRNA Nano-sized materials Nanoparticles 2012 10 5 2012 11 12 2012 12 3 2012 12 10 2012 12 15 6 0 2012 12 15 6 0 2013 12 16 6 0 ppublish 23238276 S0300-483X(12)00421-0 10.1016/j.tox.2012.12.002 23200915 2013 02 12 2013 06 24 2014 04 18

1095-6859 128 3 2013 Mar Gynecol. Oncol. Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer. 506-11 10.1016/j.ygyno.2012.11.029 S0090-8258(12)00895-5 Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch superfamily genes. We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch superfamily members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II-IV HGS-OvCa from the TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA-mRNA interaction. There were significant inverse relationships between methylation status and mRNA expression for PPARG, CCND1, and RUNX1. For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1, PPARG, and RUNX1. By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1, PPARG, and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS. Epigenetic alterations of multiple Notch target genes and pathway interacting genes (PPARG, CCND1, and RUNX1) may relate to activation of this pathway and poor survival of patients with HGS-OvCa. Copyright © 2012 Elsevier Inc. All rights reserved. Ivan Cristina C Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Hu Wei W Bottsford-Miller Justin J Zand Behrouz B Dalton Heather J HJ Liu Tao T Huang Jie J Nick Alpa M AM Lopez-Berestein Gabriel G Coleman Robert L RL Baggerly Keith A KA Sood Anil K AK eng CA109298 CA NCI NIH HHS United States CA128797 CA NCI NIH HHS United States P30 CA016672 CA NCI NIH HHS United States P50 CA083639 CA NCI NIH HHS United States P50 CA083639 CA NCI NIH HHS United States P50 CA098258 CA NCI NIH HHS United States RC2GM092599 GM NIGMS NIH HHS United States T32 CA101642 CA NCI NIH HHS United States U54 CA 151668 CA NCI NIH HHS United States U54 CA151668 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2012 11 28

United States Gynecol Oncol 0365304 0090-8258 0 CCND1 protein, human 0 Core Binding Factor Alpha 2 Subunit 0 MicroRNAs 0 PPAR gamma 0 RNA, Messenger 0 RUNX1 protein, human 0 Receptors, Notch 136601-57-5 Cyclin D1 IM Nat Rev Cancer. 2004 Jan;4(1):61-70 14708026 Mol Cell. 1999 Jun;3(6):799-804 10394368 J Biol Chem. 2005 Jul 15;280(28):26517-25 15857827 Int J Gynecol Cancer. 2007 Mar-Apr;17(2):418-25 17316361 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 J Clin Oncol. 2008 Feb 20;26(6):995-1005 18195328 Hum Pathol. 2009 May;40(5):705-13 19157507 Gynecol Oncol. 2010 Jul;118(1):81-7 20421130 J Cell Mol Med. 2010 Sep;14(9):2240-9 20345848 Biochem Biophys Res Commun. 2011 Mar 18;406(3):389-95 21329655 Nature. 2011 Jun 30;474(7353):609-15 21720365 Horm Cancer. 2010 Dec;1(6):277-90 21761359 Br J Cancer. 2011 Nov 22;105(11):1741-9 22033272 Clin Colorectal Cancer. 2011 Dec;10(4):340-7 21752725 Methods Mol Biol. 2012;863:253-69 22359298 Cancer. 2012 Jun 15;118(12):3087-94 22072418 FEBS Lett. 2012 Jul 30;586(16):2382-8 22677169 Core Binding Factor Alpha 2 Subunit biosynthesis genetics Cyclin D1 biosynthesis genetics Cystadenocarcinoma, Serous genetics metabolism pathology DNA Methylation Epigenomics methods Female Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics Ovarian Neoplasms genetics metabolism pathology PPAR gamma biosynthesis genetics RNA, Messenger genetics Receptors, Notch biosynthesis genetics Survival Analysis NIHMS462489 PMC3645276 2012 9 18 2012 11 13 2012 11 15 2012 11 28 2012 12 4 6 0 2012 12 4 6 0 2013 6 26 6 0 ppublish S0090-8258(12)00895-5 10.1016/j.ygyno.2012.11.029 23200915 PMC3645276 NIHMS462489 23159372 2013 03 13 2013 08 26 2014 09 07

1879-016X 138 1 2013 Apr Pharmacol. Ther. Epigenetic modifications by dietary phytochemicals: implications for personalized nutrition. 1-17 10.1016/j.pharmthera.2012.11.002 S0163-7258(12)00236-7 In the last two decades, the study of epigenetic modification emerged as one of the major areas of cancer treatment targeted by dietary phytochemicals. Recent studies with various types of cancers revealed that the epigenetic modifications are associated with the food source corresponds to dietary phytochemicals. The dietary phytochemicals have been used in Asian countries for thousands of years to cure several diseases including cancer. They have been reported to modulate the several biological processes including histone modification, DNA methylation and non-coding microRNA expression. These events play a vital role in carcinogenesis. Various studies suggest that a number of dietary compounds present in vegetables, spices and other herbal products have epigenetic targets in cancer cells. Dietary phytochemicals have been reported to repair DNA damage by enhancing histone acetylation that helps to restrain cell death, and also alter DNA methylation. These phytochemicals are able to modulate epigenetic modifications and their targets to cure several cancers. Epigenetic aberrations dynamically contribute to cancer pathogenesis. Given the individualized traits of epigenetic biomarkers, the personalized nutrition will help us to prevent various types of cancer. In this review, we will discuss the effect of dietary phytochemicals on genetic and epigenetic modifications and how these modifications help to prevent various types of cancers and improve health outcomes. Copyright © 2012 Elsevier Inc. All rights reserved. Shankar Sharmila S Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, The University of Kansas Cancer Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. Kumar Dhruv D Srivastava Rakesh K RK eng R01 CA114469 CA NCI NIH HHS United States R01 CA125262 CA NCI NIH HHS United States R01CA114469 CA NCI NIH HHS United States R01CA125262 CA NCI NIH HHS United States R01CA125262-02S1 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Review 2012 11 16

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16425281 Animals DNA Methylation Diet Epigenomics Histones metabolism Humans Neoplasms genetics metabolism prevention & control Nutritional Physiological Phenomena Plants chemistry RNA, Untranslated genetics NIHMS593957 PMC4153856 2012 10 31 2012 11 1 2012 11 16 2012 11 20 6 0 2012 11 20 6 0 2013 8 27 6 0 ppublish S0163-7258(12)00236-7 10.1016/j.pharmthera.2012.11.002 23159372 PMC4153856 NIHMS593957 23140160 2012 11 12 2013 04 25

1045-4403 22 3 2012 Crit. Rev. Eukaryot. Gene Expr. MicroRNAs in human lymphoblastoid cell lines. 189-96 Human lymphoblastoid cell lines (LCLs) are generated by EBV-mediated B-cell transformation to provide unlimited genomic resources for human genetics and immunological studies. The LCL is a good in vitro cell model for assessing population differences in the basal expression of genes and miRNAs as well as in cellular responses to various stimulators. Recently, the utility of LCLs was extended to pharmacogenomic studies to discover genetic factors underlying individual variations in response to chemicals and environmental stresses. Although LCLs represent generally lymphoid tissue-specific biological characteristics, genomic signatures of LCLs can distinguish patients with brain-related diseases and nonlymphoid tumors from normal controls. MicroRNA is known to be an epigenetic transcriptional regulator, and its expression is induced in abnormal conditions such as perturbagen-stimulated, virus-infected, or cancer cells. The epigenetic regulation of gene expression mediated by microRNA and DNA methylation is important for understanding the pathogenesis of cancers and complex diseases as well as discovering for therapeutic targets. For integrative genomic analyses, LCLs can be utilized to generate cellular phenotypes and various genomic data (e.g., SNP, CNV, transcriptome, methylome, etc.), which can be linked to clinical information of donors. Here, we discuss miRNA-mediated gene expression in LCLs and its application to disease genomics and global transcriptional regulatory machinery studies. Shim Sung-Mi SM National Biobank of Korea, Center for Genome Science, Korea National Institute of Health, Korea Centers for Disease Control and Prevention, 200 Osongsaengmyung-2-ro, Osong-eup, Chungwon-gun, Chungbuk-do, 363-951, South Korea. Nam Hye-Young HY Lee Jae-Eun JE Kim Jun-Woo JW Han Bok-Ghee BG Jeon Jae-Pil JP eng Journal Article Research Support, Non-U.S. Gov't Review

United States Crit Rev Eukaryot Gene Expr 9007261 1045-4403 0 MicroRNAs IM B-Lymphocytes cytology metabolism virology Cell Line, Transformed Cell Transformation, Viral Databases, Genetic Epigenesis, Genetic Gene Expression Regulation Herpesvirus 4, Human physiology Humans MicroRNAs genetics metabolism Transcriptome 2012 11 13 6 0 2012 11 13 6 0 2013 4 26 6 0 ppublish 32f018b6385e752a,3a7b3fce2d32491c 23140160 23125218 2013 02 06 2013 04 03 2013 11 21

1460-2180 34 2 2013 Feb Carcinogenesis MicroRNA-152 targets DNA methyltransferase 1 in NiS-transformed cells via a feedback mechanism. 446-53 10.1093/carcin/bgs343 Nickel (Ni) compounds are well-recognized human carcinogens, yet the molecular mechanisms by which they cause human cancer are still not well understood. MicroRNAs (miRNAs), which are small non-coding RNAs, are involved in diverse biological functions and carcinogenesis. In previous study, we identified upregulation of DNA methyltransferase 1 (DNMT1) expression in nickel sulfide (NiS)-transformed human bronchial epithelial (16HBE) cells. Here, we investigated whether some miRNAs are aberrantly expressed and targets DNMT1 in NiS-transformed cells. Our results showed that the expression of miRNA-152 (miR-152) was specifically downregulated in NiS-transformed cells via promoter DNA hypermethylation, whereas ectopic expression of miR-152 in NiS-transformed cells resulted in a marked reduction of DNMT1 expression. Further experiments revealed that miR-152 directly downregulated DNMT1 expression by targeting the 3' untranslated regions of its transcript. Interestingly, treatment of DNMT inhibitor, 5-aza-2-deoxycytidine, or depletion of DNMT1 led to increased miR-152 expression by reversion of promoter hypermethylation, DNMT1 and MeCP2 binding to miR-152 promoter in NiS-transformed cells. Moreover, inhibition of miR-152 expression in 16HBE cells could increase DNMT1 expression and result in an increase in DNA methylation, DNMT1 and MeCP2 binding to miR-152 promoter, indicating an interaction between miR-152 and DNMT1 is regulated by a double-negative circuit. Furthermore, ectopic expression of miR-152 in NiS-transformed cells led to a significant decrease of cell growth. Conversely, inhibition of miR-152 expression in 16HBE cells significantly increased cell growth. Taken together, these observations demonstrate a crucial functional crosstalk between miR-152 and the DNMT1 via a feedback loop involved in NiS-induced malignant transformation. Ji Weidong W Department of Urology, Minimally Invasive Surgery Center, The First Affiliated Hospital of Guangzhou Medical College, Guangdong Provincial Key Laboratory of Urology, 1 Kangda Road, Guangzhou 510230, China. Yang Lei L Yuan Jianhui J Yang Linqing L Zhang Mei M Qi Defeng D Duan Xiaolu X Xuan Aiguo A Zhang Wenjuan W Lu Jiachun J Zhuang Zhixiong Z Zeng Guohua G eng Journal Article Research Support, Non-U.S. Gov't 2012 11 03

England Carcinogenesis 8008055 0143-3334 0 3' Untranslated Regions 0 Carcinogens 0 MicroRNAs 0 RNA, Messenger 16812-54-7 nickel sulfide 7OV03QG267 Nickel EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 IM 3' Untranslated Regions genetics Apoptosis drug effects Blotting, Western Bronchi cytology drug effects metabolism Carcinogens pharmacology Cell Proliferation drug effects Cell Transformation, Neoplastic drug effects genetics Cells, Cultured Chromatin Immunoprecipitation DNA (Cytosine-5-)-Methyltransferase antagonists & inhibitors genetics metabolism DNA Methylation Feedback, Physiological drug effects Humans MicroRNAs genetics Nickel adverse effects RNA, Messenger genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction 2012 11 3 2012 11 24 2012 11 6 6 0 2012 11 6 6 0 2013 4 4 6 0 ppublish bgs343 10.1093/carcin/bgs343 23125218 23112837 2012 10 31 2013 04 23 2013 11 14

1932-6203 7 10 2012 PLoS ONE MicroRNA-200 family modulation in distinct breast cancer phenotypes. e47709 10.1371/journal.pone.0047709 The epithelial to mesenchymal transition (EMT) contributes to tumor invasion and metastasis in a variety of cancer types. In human breast cancer, gene expression studies have determined that basal-B/claudin-low and metaplastic cancers exhibit EMT-related characteristics, but the molecular mechanisms underlying this observation are unknown. As the family of miR-200 microRNAs has been shown to regulate EMT in normal tissues and cancer, here we evaluated whether the expression of the miR-200 family (miR-200f) and their epigenetic state correlate with EMT features in human breast carcinomas. We analyzed by qRT-PCR the expression of miR-200f members and various EMT-transcriptional inducers in a series of 70 breast cancers comprising an array of phenotypic subtypes: estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative (TN), including a subset of metaplastic breast carcinomas (MBCs) with sarcomatous (homologous or heterologous) differentiation. No MBCs with squamous differentiation were included. The DNA methylation status of miR-200f loci in tumor samples were inspected using Sequenom MassArray® MALDI-TOF platform. We also used two non-tumorigenic breast basal cell lines that spontaneously undergo EMT to study the modulation of miR-200f expression during EMT in vitro. We demonstrate that miR-200f is strongly decreased in MBCs compared with other cancer types. TN and HER2+ breast cancers also exhibited lower miR-200f expression than ER+ tumors. Significantly, the decreased miR-200f expression found in MBCs is accompanied by an increase in the expression levels of EMT-transcriptional inducers, and hypermethylation of the miR-200c-141 locus. Similar to tumor samples, we demonstrated that downregulation of miR-200f and hypermethylation of the miR-200c-141 locus, together with upregulation of EMT-transcriptional inducers also occur in an in vitro cellular model of spontaneous EMT. Thus, the expression and methylation status of miR-200f could be used as hypothetical biomarkers to assess the occurrence of EMT in breast cancer. Castilla María Ángeles MÁ Department of Pathology, Instituto de Biomedicina de Sevilla-CSIC-Universidad de Sevilla, Hospital Universitario Virgen del Rocío, Seville, Spain. Díaz-Martín Juan J Sarrió David D Romero-Pérez Laura L López-García María Ángeles MÁ Vieites Begoña B Biscuola Michele M Ramiro-Fuentes Susana S Isacke Clare M CM Palacios José J eng Journal Article Research Support, Non-U.S. Gov't 2012 10 24

United States PLoS One 101285081 1932-6203 0 MIRN200 microRNA, human 0 MicroRNAs 9007-49-2 DNA IM Genome Res. 2011 Dec;21(12):2026-37 21873453 PLoS One. 2011;6(11):e27840 22132151 Stem Cells. 2012 Feb;30(2):292-303 22102611 Mod Pathol. 2012 Feb;25(2):178-84 22080057 Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2778-83 21633010 J Mammary Gland Biol Neoplasia. 2012 Mar;17(1):65-77 22350980 Oncogene. 2012 Apr 19;31(16):2062-74 21874049 Breast Cancer Res. 2010;12(5):R68 20813035 Oncogene. 2012 Sep 20;31(38):4182-95 22231446 Oncogene. 2013 Jan 17;32(3):296-306 22370643 Nat Cell Biol. 2000 Feb;2(2):76-83 10655586 Nature. 2000 Aug 17;406(6797):747-52 10963602 Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10869-74 11553815 J Cell Sci. 2003 Feb 1;116(Pt 3):499-511 12508111 Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 12829800 J Pathol. 2004 Oct;204(2):131-9 15376261 Histopathology. 2006 Jul;49(1):10-21 16842242 Cancer Cell. 2006 Dec;10(6):515-27 17157791 Nat Rev Cancer. 2007 Jun;7(6):415-28 17508028 J Pathol. 2008 Jan;214(1):25-37 17973239 Oncogene. 2007 Dec 13;26(57):7859-71 17603561 Cancer Res. 2008 Feb 15;68(4):989-97 18281472 Nat Cell Biol. 2008 May;10(5):593-601 18376396 Cell. 2008 May 16;133(4):704-15 18485877 EMBO Rep. 2008 Jun;9(6):582-9 18483486 Clin Exp Metastasis. 2008;25(6):629-42 18461285 Trends Cell Biol. 2008 Aug;18(8):357-9 18585040 Cancer Res. 2008 Oct 1;68(19):7846-54 18829540 Cell. 2009 Jan 23;136(2):215-33 19167326 Am J Pathol. 2009 May;174(5):1588-93 19342369 Cancer Res. 2009 May 15;69(10):4116-24 19435916 Breast Cancer Res. 2009;11(1):R3 19152687 J Clin Invest. 2009 Jun;119(6):1417-9 19487817 Cell Mol Life Sci. 2009 May;66(10):1682-99 19153653 J Biol Chem. 2009 Nov 27;284(48):33019-29 19801681 Cell. 2009 Nov 25;139(5):871-90 19945376 PLoS One. 2010;5(1):e8697 20084174 J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):117-34 20490631 J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):235-52 20521089 EMBO Rep. 2010 Sep;11(9):670-7 20706219 Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15449-54 20713713 Mol Endocrinol. 2011 Feb;25(2):199-211 20861225 Int J Cancer. 2011 Mar 15;128(6):1327-34 20473948 Cell Stem Cell. 2011 Feb 4;8(2):149-63 21295272 FEBS J. 2011 May;278(10):1598-609 21395977 Annu Rev Cell Dev Biol. 2011;27:347-76 21740232 Breast Cancer Res. 2011;13(2):R45 21501518 Breast Cancer Res Treat. 2011 Dec;130(3):735-45 21409395 Hepatology. 2011 Dec;54(6):2025-35 21837748 Breast metabolism pathology Breast Neoplasms genetics pathology Cell Line, Tumor DNA genetics DNA Methylation Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics Phenotype Promoter Regions, Genetic PMC3480416 2012 6 19 2012 9 14 2012 10 24 2012 11 1 6 0 2012 11 1 6 0 2013 4 24 6 0 ppublish 10.1371/journal.pone.0047709 PONE-D-12-17655 23112837 PMC3480416 23069658 2013 08 30 2013 11 04 2014 08 06

1476-5594 32 35 2013 Aug 29 Oncogene Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells. 4130-8 10.1038/onc.2012.425 Although prostate cancer (CaP) is the most frequently diagnosed malignant tumor in American men, the mechanisms underlying the development and progression of CaP remain largely unknown. Recent studies have shown that downregulation of the microRNA miR-124 occurs in several types of human cancer, suggesting a tumor suppressive function of miR-124. Until now, however, it has been unclear whether miR-124 is associated with CaP. In the present study, we completed a series of experiments to understand the functional role of miR-124 in CaP. We detected the expression level of miR-124 in clinical CaP tissues, evaluated the influence of miR-124 on the growth of CaP cells and investigated the mechanism underlying the dysregulation of miR-124. We found that (i) miR-124 directly targets the androgen receptor (AR) and subsequently induces an upregulation of p53; (ii) miR-124 is significantly downregulated in malignant prostatic cells compared to benign cells, and DNA methylation causes the reduced expression of miR-124; and (iii) miR-124 can inhibit the growth of CaP cells in vitro and in vivo. Data from this study revealed that loss of miR-124 expression is a common event in CaP, which may contribute to the pathogenesis of CaP. Our studies also suggest that miR-124 is a potential tumor suppressive gene in CaP, and restoration of miR-124 expression may represent a novel strategy for CaP therapy. Shi X-B XB Department of Urology, University of California, Davis, School of Medicine, Sacramento, CA 95817, USA. Xue L L Ma A-H AH Tepper C G CG Gandour-Edwards R R Kung H-J HJ deVere White R W RW eng 1R01CA136597 CA NCI NIH HHS United States CA136597 CA NCI NIH HHS United States P30 CA093373 CA NCI NIH HHS United States R01 CA136597 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2012 10 15

England Oncogene 8711562 0950-9232 0 AR protein, human 0 MIRN124 microRNA, human 0 MicroRNAs 0 Receptors, Androgen IM Prostate. 2006 Jul 1;66(10):1013-28 16001449 Cell Death Differ. 2006 Sep;13(9):1554-63 16341121 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Genes Dev. 2007 Mar 1;21(5):531-6 17344415 Cancer Res. 2007 May 1;67(9):4098-103 17483320 J Biol Chem. 2007 Jul 6;282(27):19575-88 17462994 Mol Cell. 2007 Aug 3;27(3):435-48 17679093 Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19983-8 18056640 Prostate. 2008 Feb 1;68(2):210-22 18092350 Nat Struct Mol Biol. 2008 Mar;15(3):259-67 18311153 Proc Natl Acad Sci U S A. 2008 May 20;105(20):7269-74 18474871 Cancer Res. 2002 Nov 15;62(22):6606-14 12438256 Cancer Res. 2002 Feb 1;62(3):647-51 11830513 Prostate. 2001 May 15;47(3):212-21 11351351 Cancer Res. 2011 Mar 1;71(5):1956-67 21343391 Prostate. 2003 Feb 1;54(2):103-11 12497583 Nat Med. 2004 Jan;10(1):33-9 14702632 J Pathol. 2004 Feb;202(2):233-40 14743506 Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2999-3004 14973191 Cancer Lett. 2004 Mar 18;205(2):181-8 15036650 Prostate. 2004 Aug 1;60(3):257-71 15176055 Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8 18663219 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13421-6 18755897 J Cell Mol Med. 2008 Sep-Oct;12(5A):1456-65 18624768 Genome Res. 2009 Jan;19(1):92-105 18955434 Int J Cancer. 2009 May 15;124(10):2367-74 19165869 Genes Dev. 2009 Apr 1;23(7):862-76 19293287 Cancer Res. 2009 May 15;69(10):4443-53 19435910 Cancer Metastasis Rev. 2009 Dec;28(3-4):369-78 20012925 Carcinogenesis. 2010 May;31(5):766-76 19843643 Cancer Cell. 2010 Jul 13;18(1):23-38 20609350 Int J Biochem Cell Biol. 2010 Aug;42(8):1348-54 20227518 Int J Cancer. 2010 Sep 1;127(6):1363-72 20073067 Prostate. 2011 Apr;71(5):538-49 20886540 Cancer Res. 2011 Feb 15;71(4):1208-13 21285252 Nat Protoc. 2008;3(6):1101-8 18546601 CA Cancer J Clin. 2011 Jul-Aug;61(4):212-36 21685461 PLoS One. 2011;6(9):e24922 21949788 Cancer Res. 1993 Nov 15;53(22):5512-6 8221692 Cancer Res. 1995 Nov 15;55(22):5195-9 7585573 Cell Growth Differ. 1996 Nov;7(11):1571-8 8930407 Diagn Mol Pathol. 1996 Dec;5(4):271-8 8955619 Cancer Res. 1997 Jan 15;57(2):314-9 9000575 Eur Urol. 1997;31(1):1-6 9032526 Int J Oncol. 1999 Mar;14(3):495-500 10024682 Cancer Res. 1999 May 15;59(10):2329-31 10344738 Cell. 2005 Jan 14;120(1):15-20 15652477 Cancer Res. 2006 Mar 15;66(6):2980-9 16540646 Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5156-61 15790678 Ann N Y Acad Sci. 2005 Dec;1061:77-93 16467259 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Animals Apoptosis Cell Line, Tumor Cell Proliferation DNA Methylation Down-Regulation Genes, Tumor Suppressor physiology Humans Male Mice MicroRNAs physiology Prostatic Neoplasms genetics pathology prevention & control Receptors, Androgen genetics Xenograft Model Antitumor Assays NIHMS587770 PMC4111479 2012 3 15 2012 7 10 2012 7 31 2012 10 15 2012 10 17 6 0 2012 10 17 6 0 2013 11 5 6 0 ppublish onc2012425 10.1038/onc.2012.425 23069658 PMC4111479 NIHMS587770 23056006 2012 10 11 2012 10 12 2013 08 13

1664-8021 3 2012 Front Genet Role of CTCF in the regulation of microRNA expression. 186 10.3389/fgene.2012.00186 MicroRNAs (miRNAs) are small non-coding RNAs that regulate expression of various target genes. miRNAs are expressed in a tissue-specific manner and play important roles in cell proliferation, apoptosis, and differentiation. Epigenetic alterations such as DNA methylation and histone modification are essential for chromatin remodeling and regulation of gene expression including miRNAs. The CCCTC-binding factor, CTCF, is known to bind insulators and exhibits an enhancer-blocking and barrier function, and more recently, it also contributes to the three-dimensional organization of the genome. CTCF can also serve as a barrier against the spread of DNA methylation and histone repressive marks over promoter regions of tumor suppressor genes. Recent studies have shown that CTCF is also involved in the regulation of miRNAs such as miR-125b1, miR-375, and the miR-290 cluster in cancer cells and stem cells. miR-125b1 is a candidate of tumor suppressor and is silenced in breast cancer cells. On the other hand, miR-375 may have oncogenic function and is overexpressed in breast cancer cells. CTCF is involved in the regulation of both miR-125b1 and miR-375, indicating that there are various patterns of CTCF-associated epigenetic regulation of miRNAs. CTCF may also play a key role in the pluripotency of cells through the regulation of miR-290 cluster. These observations suggest that CTCF-mediated regulation of miRNAs could be a novel approach for cancer therapy and regenerative medicine. Saito Yoshimasa Y Division of Pharmacotherapeutics, Faculty of Pharmacy, Keio University Tokyo, Japan. Saito Hidetsugu H eng Journal Article 2012 09 25

Switzerland Front Genet 101560621 1664-8021 Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15472-7 17875987 Epigenetics. 2011 Sep 1;6(9):1068-77 21814038 J Pathol. 2008 Jan;214(1):17-24 17948228 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Cell. 2008 Jun 13;133(6):1106-17 18555785 Am J Pathol. 1999 Dec;155(6):1811-5 10595909 Dev Cell. 2003 Aug;5(2):351-8 12919684 Oncogene. 2004 Jul 29;23(34):5858-63 15184869 Nature. 2005 Jun 9;435(7043):839-43 15944709 Cancer Res. 2005 Jun 15;65(12):5112-22 15958555 RNA. 2005 Aug;11(8):1245-57 15987809 Cancer Cell. 2006 Jun;9(6):435-43 16766263 J Biol Chem. 2007 Jan 12;282(2):1479-86 17110380 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Cancer Res. 2007 Mar 15;67(6):2577-85 17363576 Nature. 2007 Jun 28;447(7148):1130-4 17554337 J Clin Invest. 2007 Aug;117(8):2059-66 17671640 Nat Rev Cancer. 2007 Sep;7(9):659-72 17721431 Cell Cycle. 2008 Aug 15;7(16):2591-600 18719384 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 J Gastroenterol. 2009;44 Suppl 19:18-22 19148788 Nat Biotechnol. 2009 May;27(5):459-61 19363475 Mol Cell. 2009 May 15;34(3):271-84 19450526 Oncogene. 2009 Jul 30;28(30):2738-44 19503096 Cell. 2009 Jun 26;137(7):1194-211 19563753 Cancer Res. 2010 Nov 15;70(22):9175-84 20978187 Cancer Res. 2011 May 15;71(10):3552-62 21444677 Biochem Cell Biol. 2011 Oct;89(5):479-88 21846316 Nat Rev Genet. 2011 Dec;12(12):861-74 22094949 Development. 2012 Mar;139(6):1045-57 22354838 BMC Cancer. 2012;12:40 22277129 Curr Top Dev Biol. 2008;80:337-60 17950379 Nat Struct Mol Biol. 2008 Mar;15(3):268-79 18311151 Nat Struct Mol Biol. 2008 Mar;15(3):259-67 18311153 Nucleic Acids Res. 2011 May;39(9):3574-81 21247880 Mol Cancer. 2007;6:60 17894887 PMC3457075 CTCF cancer cell embryonic stem cell miR-125b1 miR-290 cluster miR-375 microRNA 2012 6 08 2012 9 03 2012 9 25 2012 10 12 6 0 2012 10 12 6 0 2012 10 12 6 1 epublish 10.3389/fgene.2012.00186 23056006 PMC3457075 23000897 2012 10 05 2012 11 26 2014 09 03

1476-4687 490 7418 2012 Oct 4 Nature Comprehensive molecular portraits of human breast tumours. 61-70 10.1038/nature11412 We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer. Cancer Genome Atlas Network eng K08 CA148912 CA NCI NIH HHS United States P30 CA016058 CA NCI NIH HHS United States P30 CA016086 CA NCI NIH HHS United States P30 CA016672 CA NCI NIH HHS United States P50 CA058223 CA NCI NIH HHS United States P50 CA116201 CA NCI NIH HHS United States P50CA116201 CA NCI NIH HHS United States P50CA58223 CA NCI NIH HHS United States R01 LM009722 LM NLM NIH HHS United States U01 CA084955 CA NCI NIH HHS United States U24 CA143799 CA NCI NIH HHS United States U24 CA143848 CA NCI NIH HHS United States U24 CA143866 CA NCI NIH HHS United States U24CA143799 CA NCI NIH HHS United States U24CA143835 CA NCI NIH HHS United States U24CA143840 CA NCI NIH HHS United States U24CA143845 CA NCI NIH HHS United States U24CA143848 CA NCI NIH HHS United States U24CA143858 CA NCI NIH HHS United States U24CA143866 CA NCI NIH HHS United States U24CA143867 CA NCI NIH HHS United States U24CA143882 CA NCI NIH HHS United States U24CA143883 CA NCI NIH HHS United States U24CA144025 CA NCI NIH HHS United States U54 HG004028 HG NHGRI NIH HHS United States U54HG003079 HG NHGRI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2012 09 23

England Nature 0410462 0028-0836 0 GATA3 Transcription Factor 0 GATA3 protein, human 0 MicroRNAs 0 RNA, Messenger 0 RNA, Neoplasm 0 Receptors, Estrogen 0 Retinoblastoma Protein EC 2.7.1.- Phosphatidylinositol 3-Kinases EC 2.7.1.137 PIK3CA protein, human EC 2.7.11.25 MAP Kinase Kinase Kinase 1 EC 2.7.11.25 MAP3K1 protein, human IM Blood. 2011 Dec 8;118(24):6239-46 21998214 N Engl J Med. 2011 Dec 29;365(26):2497-506 22150006 N Engl J Med. 2012 Jan 12;366(2):109-19 22149875 Genome Res. 2012 Feb;22(2):398-406 21908773 Cancer Discov. 2011 Jul;1(2):170-85 21984976 Oncogene. 2001 Apr 26;20(18):2225-34 11402317 Nature. 2000 Aug 17;406(6797):747-52 10963602 Nature. 2012 Jun 21;486(7403):395-9 22495314 Nature. 2002 Jan 31;415(6871):530-6 11823860 Science. 2002 Dec 6;298(5600):1911-2 12471242 Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8418-23 12829800 J Natl Cancer Inst. 2003 Oct 1;95(19):1482-5 14519755 Nat Med. 2004 Jun;10(6):594-601 15156201 Oncogene. 2004 Oct 7;23(46):7669-78 15361840 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GATA3 Transcription Factor genetics Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, BRCA1 Genes, Neoplasm genetics Genes, erbB-2 genetics Genes, p53 genetics Genetic Heterogeneity Genome, Human genetics Genomics Humans MAP Kinase Kinase Kinase 1 genetics MicroRNAs genetics Mutation genetics Oligonucleotide Array Sequence Analysis Ovarian Neoplasms genetics pathology Phosphatidylinositol 3-Kinases genetics Protein Array Analysis Proteomics RNA, Messenger genetics RNA, Neoplasm genetics Receptors, Estrogen metabolism Retinoblastoma Protein genetics metabolism NIHMS393293 PMC3465532 Koboldt Daniel C DC Fulton Robert S RS McLellan Michael D MD Schmidt Heather H Kalicki-Veizer Joelle J McMichael Joshua F JF Fulton Lucinda L LL Dooling David J DJ Ding Li L Mardis Elaine R ER Wilson Richard K RK Ally Adrian A Balasundaram Miruna M Butterfield Yaron S N YS Carlsen Rebecca R Carter Candace C Chu Andy A Chuah Eric E Chun Hye-Jung E HJ Coope Robin J N RJ Dhalla Noreen N Guin Ranabir R Hirst Carrie C Hirst Martin M Holt Robert A RA Lee Darlene D Li Haiyan I HI Mayo Michael M Moore Richard A RA Mungall Andrew J AJ Pleasance Erin E Robertson A Gordon A Schein Jacqueline E JE Shafiei Arash A Sipahimalani Payal P Slobodan Jared R JR Stoll Dominik D Tam Angela A Thiessen Nina N Varhol Richard J RJ Wye Natasja N Zeng Thomas T Zhao Yongjun Y Birol Inanc I Jones Steven J M SJ Marra Marco A MA Cherniack Andrew D AD Saksena Gordon G Onofrio Robert C RC Pho Nam H NH Carter Scott L SL Schumacher Steven E SE Tabak Barbara B Hernandez Bryan B Gentry Jeff J Nguyen Huy H Crenshaw Andrew A Ardlie Kristin K Beroukhim Rameen R Winckler Wendy W Getz Gad G Gabriel Stacey B SB Meyerson Matthew M Chin Lynda L Park Peter J PJ Kucherlapati Raju R Hoadley Katherine A KA Auman J Todd J Fan Cheng C Turman Yidi J YJ Shi Yan Y Li Ling L Topal Michael D MD He Xiaping X Chao Hann-Hsiang HH Prat Aleix A Silva Grace O GO Iglesia Michael D MD Zhao Wei W Usary Jerry J Berg Jonathan S JS Adams Michael M Booker Jessica J Wu Junyuan J Gulabani Anisha A Bodenheimer Tom T Hoyle Alan P AP Simons Janae V JV Soloway Matthew G MG Mose Lisle E LE Jefferys Stuart R SR Balu Saianand S Parker Joel S JS Hayes D Neil D Perou Charles M CM Malik Simeen S Mahurkar Swapna S Shen Hui H Weisenberger Daniel J DJ Triche Timothy T Jr Lai Phillip H PH Bootwalla Moiz S MS Maglinte Dennis T DT Berman Benjamin P BP Van Den Berg David J DJ Baylin Stephen B SB Laird Peter W PW Creighton Chad J CJ Donehower Lawrence A LA Getz Gad G Noble Michael M Voet Doug D Saksena Gordon G Gehlenborg Nils N DiCara Daniel D Zhang Juinhua J Zhang Hailei H Wu Chang-Jiun CJ Liu Spring Yingchun SY Lawrence Michael S MS Zou Lihua L Sivachenko Andrey A Lin Pei P Stojanov Petar P Jing Rui R Cho Juok J Sinha Raktim R Park Richard W RW Nazaire Marc-Danie MD Robinson Jim J Thorvaldsdottir Helga H Mesirov Jill J Park Peter J PJ Chin Lynda L Reynolds Sheila S Kreisberg Richard B RB Bernard Brady B Bressler Ryan R Erkkila Timo T Lin Jake J Thorsson Vesteinn V Zhang Wei W Shmulevich Ilya I Ciriello Giovanni G Weinhold Nils N Schultz Nikolaus N Gao Jianjiong J Cerami Ethan E Gross Benjamin B Jacobsen Anders A Sinha Rileen R Aksoy B Arman B Antipin Yevgeniy Y Reva Boris B Shen Ronglai R Taylor Barry S BS Ladanyi Marc M Sander Chris C Anur Pavana P Spellman Paul T PT Lu Yiling Y Liu Wenbin W Verhaak Roel R G RR Mills Gordon B GB Akbani Rehan R Zhang Nianxiang N Broom Bradley M BM Casasent Tod D TD Wakefield Chris C Unruh Anna K AK Baggerly Keith K Coombes Kevin K Weinstein John N JN Haussler David D Benz Christopher C CC Stuart Joshua M JM Benz Stephen C SC Zhu Jingchun J Szeto Christopher C CC Scott Gary K GK Yau Christina C Paull Evan O EO Carlin Daniel D Wong Christopher C Sokolov Artem A Thusberg Janita J Mooney Sean S Ng Sam S Goldstein Theodore C TC Ellrott Kyle K Grifford Mia M Wilks Christopher C Ma Singer S Craft Brian B Yan Chunhua C Hu Ying Y Meerzaman Daoud D Gastier-Foster Julie M JM Bowen Jay J Ramirez Nilsa C NC Black Aaron D AD Pyatt Robert E RE White Peter P Zmuda Erik J EJ Frick Jessica J Lichtenberg Tara M TM Brookens Robin R George Myra M MM Gerken Mark A MA Harper Hollie A HA Leraas Kristen M KM Wise Lisa J LJ Tabler Teresa R TR McAllister Cynthia C Barr Thomas T Hart-Kothari Melissa M Tarvin Katie K Saller Charles C Sandusky George G Mitchell Colleen C Iacocca Mary V MV Brown Jennifer J Rabeno Brenda B Czerwinski Christine C Petrelli Nicholas N Dolzhansky Oleg O Abramov Mikhail M Voronina Olga O Potapova Olga O Marks Jeffrey R JR Suchorska Wiktoria M WM Murawa Dawid D Kycler Witold W Ibbs Matthew M Korski Konstanty K Spychała Arkadiusz A Murawa Paweł P Brzeziński Jacek J JJ Perz Hanna H Łaźniak Radosław R Teresiak Marek M Tatka Honorata H Leporowska Ewa E Bogusz-Czerniewicz Marta M Malicki Julian J Mackiewicz Andrzej A Wiznerowicz Maciej M Le Xuan Van XV Kohl Bernard B Nguyen Viet Tien VT Thorp Richard R Nguyen Van Bang VB Sussman Howard H Bui Duc Phu DP Hajek Richard R Nguyen Phi Hung PH Tran Viet The Phuong VT Huynh Quyet Thang QT Khan Khurram Zaki KZ Penny Robert R Mallery David D Curley Erin E Shelton Candace C Yena Peggy P Ingle James N JN Couch Fergus J FJ Lingle Wilma L WL King Tari A TA Gonzalez-Angulo Ana Maria AM Mills Gordon B GB Dyer Mary D MD Liu Shuying S Meng Xiaolong X Patangan Modesto M Waldman Frederic F Stöppler Hubert H Rathmell W Kimryn W Thorne Leigh L Huang Mei M Boice Lori L Hill Ashley A Morrison Carl C Gaudioso Carmelo C Bshara Wiam W Daily Kelly K Egea Sophie C SC Pegram Mark M Gomez-Fernandez Carmen C Dhir Rajiv R Bhargava Rohit R Brufsky Adam A Shriver Craig D CD Hooke Jeffrey A JA Campbell Jamie Leigh JL Mural Richard J RJ Hu Hai H Somiari Stella S Larson Caroline C Deyarmin Brenda B Kvecher Leonid L Kovatich Albert J AJ Ellis Matthew J MJ King Tari A TA Hu Hai H Couch Fergus J FJ Mural Richard J RJ Stricker Thomas T White Kevin K Olopade Olufunmilayo O Ingle James N JN Luo Chunqing C Chen Yaqin Y Marks Jeffrey R JR Waldman Frederic F Wiznerowicz Maciej M Bose Ron R Chang Li-Wei LW Beck Andrew H AH Gonzalez-Angulo Ana Maria AM Pihl Todd T Jensen Mark M Sfeir Robert R Kahn Ari A Chu Anna A Kothiyal Prachi P Wang Zhining Z Snyder Eric E Pontius Joan J Ayala Brenda B Backus Mark M Walton Jessica J Baboud Julien J Berton Dominique D Nicholls Matthew M Srinivasan Deepak D Raman Rohini R Girshik Stanley S Kigonya Peter P Alonso Shelley S Sanbhadti Rashmi R Barletta Sean S Pot David D Sheth Margi M Demchok John A JA Shaw Kenna R Mills KR Yang Liming L Eley Greg G Ferguson Martin L ML Tarnuzzer Roy W RW Zhang Jiashan J Dillon Laura A L LA Buetow Kenneth K Fielding Peter P Ozenberger Bradley A BA Guyer Mark S MS Sofia Heidi J HJ Palchik Jacqueline D JD 2012 3 22 2012 7 11 2012 9 23 2012 9 25 6 0 2012 9 25 6 0 2012 12 10 6 0 ppublish nature11412 10.1038/nature11412 23000897 PMC3465532 NIHMS393293 22989523 2013 01 14 2013 06 18

1095-9130 59 1 2013 Jan Methods Genetic and epigenetic factors in regulation of microRNA in colorectal cancers. 138-46 10.1016/j.ymeth.2012.09.002 S1046-2023(12)00242-3 Studies on miRNA profiling revealed that a large number of them are significantly deregulated in human cancers. The molecular mechanisms of this deregulation are not totally clarified, even if genetics and epigenetics are frequently involved. Single nucleotide polymorphisms (SNPs) are the most common type of genetic variation in the human genome. A SNP into miRNA gene might affect the transcription of primary miRNA, its processing and miRNA-mRNA interaction. We investigated the distribution of sequence variants of miR-146a, miR-196a2, miR-499 and miR-149 in colorectal cancer (CRC) and their effect on miRNA expression. Each variant was identified with HRM. For miR-499 we demonstrated a significant reduction of its expression in CRC connected to a specific genotype. To evaluate the epigenetic effects on miRNA genes in CRC, we investigated the influence of DNA methylation on miR-34b, miR-34c and miR-9-1 expression. We aimed to verify the relationship between the methylation status of these miRNA genes and their relative expression in tumor samples. For the quantification of DNA methylation we adopted a method based on Differential High Resolution Melting (D-HRM). Copyright © 2012 Elsevier Inc. All rights reserved. Vinci Serena S Clinical Biochemistry, Dept. of Clinical Physiopathology, University of Florence, Italy. Gelmini Stefania S Mancini Irene I Malentacchi Francesca F Pazzagli Mario M Beltrami Cristina C Pinzani Pamela P Orlando Claudio C eng Journal Article 2012 09 16

United States Methods 9426302 1046-2023 0 MIRN34 microRNA, human 0 MIRN499 microRNA, human 0 MIRN9 microRNA, human 0 MicroRNAs IM Adult Aged Aged, 80 and over Case-Control Studies Colorectal Neoplasms genetics metabolism DNA Methylation Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Gene Frequency Genetic Association Studies Humans Male MicroRNAs genetics metabolism Middle Aged Polymorphism, Single Nucleotide Sequence Analysis, DNA methods Transition Temperature 2012 2 7 2012 8 27 2012 9 7 2012 9 16 2012 9 20 6 0 2012 9 20 6 0 2013 6 19 6 0 ppublish S1046-2023(12)00242-3 10.1016/j.ymeth.2012.09.002 22989523 22970025 2012 9 12

1792-0981 4 2 2012 Aug Exp Ther Med microRNA signature for human pancreatic cancer invasion and metastasis. 181-187 Pancreatic cancer has the poorest prognosis among all human malignant solid tumors, mainly due to its high invasive and metastatic biological features. microRNAs (miRNAs) are a group of endogenous and small non-coding RNA molecules 18-25 nucleotides in length, functioning as either tumor-suppressor genes or oncogenes. Evidence has shown that regulation of miRNAs in pancreatic cancer is associated with tumor growth, invasion, metastasis and resistance to therapy. Over the last decade, many studies have also found that there is a close relationship between miRNAs and biological characteristics of pancreatic cancer invasion and metastasis, such as the presence of cancer stem cells, epithelial-mesenchymal transition (EMT) phenotype, DNA methylation or epigenetic alteration, and the activation of some specific signaling pathways. Therefore, better understanding of the complex role of miRNAs in the development and progression of pancreatic cancer metastasis may provide new insights that could be of therapeutic consequence. In this brief review, we discuss the literature concerning the correlation between miRNAs and pancreatic cancer, focusing on miRNAs that contribute to pancreatic cancer invasion and metastasis, particularly on cancer stem cell characteristics, the EMT process, epigenetic modifications and tumor-associated signaling pathways. Cheng He H Department of Pancreatic and Hepatobiliary Surgery, Fudan University, Shanghai Cancer Center; Shi Si S Cai Xiaochen X Long Jiang J Xu Jin J Liu Chen C Yu Xianjun X ENG JOURNAL ARTICLE 2012 5 21

Exp Ther Med 101531947 1792-0981 2012 3 22 2012 5 14 2012 5 21 2012 9 13 6 0 2012 9 13 6 0 2012 9 13 6 0 ppublish 10.3892/etm.2012.585 etm-04-02-0181 22970025 PMC3439005 22949852 2012 09 05 2012 10 02 2013 05 30

1422-0067 13 8 2012 Int J Mol Sci Epigenetic effects of environmental chemicals bisphenol a and phthalates. 10143-53 10.3390/ijms130810143 The epigenetic effects on DNA methylation, histone modification, and expression of non-coding RNAs (including microRNAs) of environmental chemicals such as bisphenol A (BPA) and phthalates have expanded our understanding of the etiology of human complex diseases such as cancers and diabetes. Multiple lines of evidence from in vitro and in vivo models have established that epigenetic modifications caused by in utero exposure to environmental toxicants can induce alterations in gene expression that may persist throughout life. Epigenetics is an important mechanism in the ability of environmental chemicals to influence health and disease, and BPA and phthalates are epigenetically toxic. The epigenetic effect of BPA was clearly demonstrated in viable yellow mice by decreasing CpG methylation upstream of the Agouti gene, and the hypomethylating effect of BPA was prevented by maternal dietary supplementation with a methyl donor like folic acid or the phytoestrogen genistein. Histone H3 was found to be trimethylated at lysine 27 by BPA effect on EZH2 in a human breast cancer cell line and mice. BPA exposure of human placental cell lines has been shown to alter microRNA expression levels, and specifically, miR-146a was strongly induced by BPA treatment. In human breast cancer MCF7 cells, treatment with the phthalate BBP led to demethylation of estrogen receptor (ESR1) promoter-associated CpG islands, indicating that altered ESR1 mRNA expression by BBP is due to aberrant DNA methylation. Maternal exposure to phthalate DEHP was also shown to increase DNA methylation and expression levels of DNA methyltransferases in mouse testis. Further, some epigenetic effects of BPA and phthalates in female rats were found to be transgenerational. Finally, the available new technologies for global analysis of epigenetic alterations will provide insight into the extent and patterns of alterations between human normal and diseased tissues. In vitro models such as human embryonic stem cells may be extremely useful in bettering the understanding of epigenetic effects on human development, health and disease, because the formation of embryoid bodies in vitro is very similar to the early stage of embryogenesis. Singh Sher S Department of Life Science, College of Science, National Taiwan Normal University, Taipei 116, Taiwan; E-Mail: sher@ntnu.edu.tw. Li Steven Shoei-Lung SS eng Journal Article 2012 08 15

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1949-2553 3 9 2012 Sep Oncotarget Genetic and epigenetic loss of microRNA-31 leads to feed-forward expression of EZH2 in melanoma. 1011-25 MicroRNAs (miRs) play a key role in cancer etiology by coordinately repressing numerous target genes involved in cell proliferation, migration and invasion. The genomic region in chromosome 9p21 that encompasses miR-31 is frequently deleted in solid cancers including melanoma; however the expression and functional role of miR-31 has not been previously studied in melanoma. Here, we queried the expression status and performed functional characterization of miR-31 in melanoma tissues and cell lines. We found that down-regulation of miR-31 was a common event in melanoma tumors and cell lines and was associated with genomic loss in a subset of samples. Down-regulation of miR-31 gene expression was also a result of epigenetic silencing by DNA methylation, and via EZH2-mediated histone methylation. Ectopic overexpression of miR-31 in various melanoma cell lines inhibited cell migration and invasion. miR-31 targets include oncogenic kinases such as SRC, MET, NIK (MAP3K14) and the melanoma specific oncogene RAB27a. Furthermore, miR-31 overexpression resulted in down-regulation of EZH2 and a de-repression of its target gene rap1GAP; increased expression of EZH2 was associated with melanoma progression and overall patient survival. Taken together, our study supports a tumor suppressor role for miR-31 in melanoma and identifies novel therapeutic targets. Asangani Irfan A IA Michigan Center for Translational Pathology. Harms Paul W PW Dodson Lois L Pandhi Mithil M Kunju Lakshmi P LP Maher Christopher A CA Fullen Douglas R DR Johnson Timothy M TM Giordano Thomas J TJ Palanisamy Nallasivam N Chinnaiyan Arul M AM eng Journal Article Research Support, Non-U.S. Gov't

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1868-7083 4 1 2012 Clin Epigenetics Epigenetic alterations in preneoplastic and neoplastic lesions of the cervix. 13 10.1186/1868-7083-4-13 Cervical cancer (CC) is one of the most malignant tumors and the second or third most common type of cancer in women worldwide. The association between human papillomavirus (HPV) and CC is widely known and accepted (99.7% of cases). At present, the pathogenesis mechanisms of CC are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic alterations. In the past, it was generally thought that genetic mutation was a key event of tumor pathogenesis, especially somatic mutation of tumor suppressor genes. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in DNA sequence. Specific epigenetic processes include DNA methylation, chromotin remodeling, histone modification, and microRNA regulations. These alterations, in combination or individually, make it possible to establish the methylation profiles, histone modification maps, and expression profiles characteristic of this pathology, which become useful tools for screening, early detection, or prognostic markers in cervical cancer. This paper reviews recent epigenetics research progress in the CC study, and tries to depict the relationships between CC and DNA methylation, histone modification, as well as microRNA regulations. Saavedra Kathleen P KP Universidad de La Frontera, School of Medicine, Department of Pathology, Molecular Pathology Laboratory, BIOREN-CEGIN, Temuco, Chile. jcroa@ufro.cl. Brebi Priscilla M PM Roa Juan Carlos S JC eng Journal Article 2012 08 31

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1532-0480 45 6 2012 Dec J Biomed Inform Synergistic effect of different levels of genomic data for cancer clinical outcome prediction. 1191-8 10.1016/j.jbi.2012.07.008 S1532-0464(12)00105-0 There have been many attempts in cancer clinical-type classification by using a dataset from a number of molecular layers of biological system. Despite these efforts, however, it still remains difficult to elucidate the cancer phenotypes because the cancer genome is neither simple nor independent but rather complicated and dysregulated by multiple molecular mechanisms. Recently, heterogeneous types of data, generated from all molecular levels of 'omic' dimensions from genome to phenome, for instance, copy number variants at the genome level, DNA methylation at the epigenome level, and gene expression and microRNA at the transcriptome level, have become available. In this paper, we propose an integrated framework that uses multi-level genomic data for prediction of clinical outcomes in brain cancer (glioblastoma multiforme, GBM) and ovarian cancer (serous cystadenocarcinoma, OV). From empirical comparison results on individual genomic data, we provide some preliminary insights about which level of data is more informative to a given clinical-type classification problem and justify these perceptions with the corresponding biological implications for each type of cancer. For GBM, all clinical outcomes had a better the area under the curve (AUC) of receiver operating characteristic when integrating multi-layers of genomic data, 0.876 for survival to 0.832 for recurrence. Moreover, the better AUCs were achieved from the integration approach for all clinical outcomes in OV as well, ranging from 0.787 to 0.893. We found that the opportunity for success in prediction of clinical outcomes in cancer was increased when the prediction was based on the integration of multi-layers of genomic data. This study is expecting to improve comprehension of the molecular pathogenesis and underlying biology of both cancer types. Copyright © 2012 Elsevier Inc. All rights reserved. Kim Dokyoon D Seoul National University Biomedical Informatics (SNUBI), Div. of Biomedical Informatics, Seoul National University College of Medicine, Seoul 110-799, Republic of Korea. Shin Hyunjung H Song Young Soo YS Kim Ju Han JH eng Journal Article Research Support, Non-U.S. Gov't 2012 08 15

United States J Biomed Inform 100970413 1532-0464 0 MicroRNAs IM J Biomed Inform. 2012 Dec;45(6):1199-201 23117078 Area Under Curve Brain Neoplasms genetics DNA Methylation Databases, Factual Female Genome, Human Genomics methods Glioblastoma genetics Humans MicroRNAs genetics Neoplasms genetics Ovarian Neoplasms genetics 2011 10 31 2012 6 20 2012 7 19 2012 8 15 2012 8 23 6 0 2012 8 23 6 0 2013 3 30 6 0 ppublish S1532-0464(12)00105-0 10.1016/j.jbi.2012.07.008 22910106 22906743 2012 09 18 2013 01 31 2013 11 21

1090-2104 426 1 2012 Sep 14 Biochem. Biophys. Res. Commun. Development of a novel microRNA promoter microarray for ChIP-on-chip assay to identify epigenetically regulated microRNAs. 33-7 10.1016/j.bbrc.2012.08.012 S0006-291X(12)01509-4 To gain a global view of epigenetic alterations around microRNA (miRNA) promoter regions, and to identify epigenetically regulated miRNAs, we developed a novel miRNA promoter microarray for chromatin immunoprecipitation (ChIP)-on-chip assay. We designed a custom oligo microarray covering regions spanning -10 to +2.5 kb of precursor miRNAs in the human genome. This microarray covers 541 miRNAs, each of which is covered by approximately 100 probes (60-mer) over its 12.5-kb genomic position, that includes predicted transcription start sites. Using this custom-made miRNA promoter microarray, we successfully performed ChIP-on-chip assay to identify miRNAs regulated by histone modification. Fifty-three miRNAs (9.8%) showed increased levels of both histone H3 acetylation and histone H3-K4 methylation in AGS gastric cancer cells treated with the DNA-methylation inhibitor 5-aza-2'-deoxycytidine and the histone deacetylase inhibitor 4-phenylbutyric acid. One of these miRNAs, miR-9, is downregulated in gastric cancer tissues and is activated by chromatin-modifying drugs, suggesting that it may be a potential target for epigenetic therapy of gastric cancer. Copyright © 2012 Elsevier Inc. All rights reserved. Saito Yoshimasa Y Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan. Suzuki Hidekazu H Taya Toshiki T Nishizawa Masafumi M Tsugawa Hitoshi H Matsuzaki Juntaro J Hirata Kenro K Saito Hidetsugu H Hibi Toshifumi T eng Journal Article Research Support, Non-U.S. Gov't 2012 08 11

United States Biochem Biophys Res Commun 0372516 0006-291X 0 Histones 0 MicroRNAs 776B62CQ27 decitabine EC 2.1.1.- DNA Modification Methylases M801H13NRU Azacitidine IM Azacitidine analogs & derivatives pharmacology Cell Line, Tumor Chromatin Immunoprecipitation methods DNA Modification Methylases antagonists & inhibitors Down-Regulation Epigenesis, Genetic Histones metabolism Humans MicroRNAs genetics Oligonucleotide Array Sequence Analysis methods Promoter Regions, Genetic Stomach Neoplasms genetics therapy 2012 8 3 2012 8 4 2012 8 11 2012 8 22 6 0 2012 8 22 6 0 2013 2 1 6 0 ppublish S0006-291X(12)01509-4 10.1016/j.bbrc.2012.08.012 22906743 22902148 2012 11 19 2013 04 15

1878-0261 6 6 2012 Dec Mol Oncol DNA methylation and microRNA dysregulation in cancer. 567-78 10.1016/j.molonc.2012.07.007 S1574-7891(12)00079-8 DNA methylation plays a key role in the silencing of numerous cancer-related genes, thereby affecting a number of vital cellular processes, including the cell cycle checkpoint, apoptosis, signal transduction, cell adhesion and angiogenesis. Also widely altered in human malignancies is the expression of microRNAs (miRNAs), a class of small noncoding RNAs that act as posttranscriptional regulators of gene expression. Furthermore, emerging evidence now supports the idea that DNA methylation is crucially involved in the dysregulation of miRNAs in cancer. This is in part the result of technological advances that enable more comprehensive analysis of miRNA expression profiles and the epigenome in cancer cells, which has led to the identification of a number of epigenetically regulated miRNAs. As with protein-coding genes, it appears that miRNA genes involved in regulating cancer-related pathways are silenced in association with CpG island hypermethylation. In addition, methylation in CpG island shore regions and DNA hypomethylation also appear to contribute to miRNA dysregulation in cancer. Aberrant DNA methylation of miRNA genes is a potentially useful biomarker for detecting cancer and predicting its outcome. Moreover, re-expression of miRNAs and the replacement of tumor suppressive miRNAs using miRNA mimics or expression vectors could be effective approaches to cancer therapy. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Suzuki Hiromu H Department of Molecular Biology, Sapporo Medical University, S1 W17, Chuo-Ku, Sapporo 060-8556, Japan. hsuzuki@sapmed.ac.jp Maruyama Reo R Yamamoto Eiichiro E Kai Masahiro M eng Journal Article Research Support, Non-U.S. Gov't Review 2012 08 10

Netherlands Mol Oncol 101308230 1574-7891 0 MicroRNAs 9007-49-2 DNA IM Animals DNA genetics DNA Methylation Gene Expression Regulation, Neoplastic Gene Silencing Humans MicroRNAs genetics Neoplasms genetics therapy 2012 6 19 2012 7 30 2012 8 10 2012 8 21 6 0 2012 8 21 6 0 2013 4 16 6 0 ppublish S1574-7891(12)00079-8 10.1016/j.molonc.2012.07.007 22902148 22879375 2012 10 24 2013 01 14 2013 11 15

1362-4962 40 19 2012 Oct Nucleic Acids Res. Discovery of multi-dimensional modules by integrative analysis of cancer genomic data. 9379-91 10.1093/nar/gks725 Recent technology has made it possible to simultaneously perform multi-platform genomic profiling (e.g. DNA methylation (DM) and gene expression (GE)) of biological samples, resulting in so-called 'multi-dimensional genomic data'. Such data provide unique opportunities to study the coordination between regulatory mechanisms on multiple levels. However, integrative analysis of multi-dimensional genomics data for the discovery of combinatorial patterns is currently lacking. Here, we adopt a joint matrix factorization technique to address this challenge. This method projects multiple types of genomic data onto a common coordinate system, in which heterogeneous variables weighted highly in the same projected direction form a multi-dimensional module (md-module). Genomic variables in such modules are characterized by significant correlations and likely functional associations. We applied this method to the DM, GE, and microRNA expression data of 385 ovarian cancer samples from the The Cancer Genome Atlas project. These md-modules revealed perturbed pathways that would have been overlooked with only a single type of data, uncovered associations between different layers of cellular activities and allowed the identification of clinically distinct patient subgroups. Our study provides an useful protocol for uncovering hidden patterns and their biological implications in multi-dimensional 'omic' data. Zhang Shihua S Program in Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA. Liu Chun-Chi CC Li Wenyuan W Shen Hui H Laird Peter W PW Zhou Xianghong Jasmine XJ eng R01GM074163 GM NIGMS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2012 08 08

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1471-2407 12 2012 BMC Cancer MicroRNA-196a promotes non-small cell lung cancer cell proliferation and invasion through targeting HOXA5. 348 10.1186/1471-2407-12-348 MicroRNAs (miRNAs) are short, non-coding RNAs (~22 nt) that play important roles in the pathogenesis of human diseases by negatively regulating gene expression. Although miR-196a has been implicated in several other cancers, its role in non-small cell lung cancer (NSCLC) is unknown. The aim of the present study was to examine the expression pattern of miR-196a in NSCLC and its clinical significance, as well as its biological role in tumor progression. Expression of miR-196a was analyzed in 34 NSCLC tissues and five NSCLC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of DNA methylation on miR-196a expression was investigated by 5-aza-2-deoxy-cytidine treatment and bisulfite sequencing. The effect of miR-196a on proliferation was evaluated by MTT and colony formation assays, and cell migration and invasion were evaluated by transwell assays. Analysis of target protein expression was determined by western blotting. Luciferase reporter plasmids were constructed to confirm the action of miR-196a on downstream target genes, including HOXA5. Differences between the results were tested for significance using Student's t-test (two-tailed). miR-196a was highly expressed both in NSCLC samples and cell lines compared with their corresponding normal counterparts, and the expression of miR-196a may be affected by DNA demethylation. Higher expression of miR-196a in NSCLC tissues was associated with a higher clinical stage, and also correlated with NSCLC lymph-node metastasis. In vitro functional assays demonstrated that modulation of miR-196a expression affected NSCLC cell proliferation, migration and invasion. Our analysis showed that miR-196a suppressed the expression of HOXA5 both at the mRNA and protein levels, and luciferase assays confirmed that miR-196a directly bound to the 3'untranslated region of HOXA5. Knockdown of HOXA5 expression in A549 cells using RNAi was shown to promote NSCLC cell proliferation, migration and invasion. Finally, we observed an inverse correlation between HOXA5 and miR-196a expression in NSCLC tissues. Our findings indicate that miR-196a is significantly up-regulated in NSCLC tissues, and regulates NSCLC cell proliferation, migration and invasion, partially via the down-regulation of HOXA5. Thus, miR-196a may represent a potential therapeutic target for NSCLC intervention. Liu Xiang-hua XH Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People's Republic of China. Lu Kai-hua KH Wang Ke-ming KM Sun Ming M Zhang Er-bao EB Yang Jin-song JS Yin Dan-dan DD Liu Zhi-li ZL Zhou Jing J Liu Zhi-jun ZJ De Wei W Wang Zhao-xia ZX eng Journal Article Research Support, Non-U.S. Gov't 2012 08 09

England BMC Cancer 100967800 1471-2407 0 HOXA5 protein, human 0 Homeodomain Proteins 0 MIRN196 microRNA, human 0 MicroRNAs IM Dev Dyn. 2000 Jan;217(1):62-74 10679930 Mol Cancer Ther. 2012 Apr;11(4):842-52 22343731 J Biol Chem. 2000 Aug 25;275(34):26551-5 10875927 Am J Pathol. 2001 Mar;158(3):955-66 11238043 Cell. 2004 Jan 23;116(2):281-97 14744438 Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6348-52 1712489 Curr Opin Hematol. 2005 May;12(3):210-6 15867577 Mol Cancer Ther. 2005 Oct;4(10):1577-84 16227408 Dev Biol. 2006 Mar 15;291(2):193-206 16515781 Am J Pathol. 2006 Oct;169(4):1312-27 17003488 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 Dev Growth Differ. 2007 May;49(4):265-75 17501904 Cancer Res. 2007 Jun 15;67(12):5806-13 17575148 Lancet Oncol. 2007 Sep;8(9):784-96 17714993 Cancer Res. 2007 Sep 1;67(17):8007-13 17804711 J Urol. 2008 Nov;180(5):2196-201 18804814 Oncogene. 2008 Nov 6;27(52):6667-78 18663355 Br J Cancer. 2009 Feb 10;100(3):470-5 19156136 Acta Biomater. 2009 Mar;5(3):842-53 19249722 Lab Invest. 2009 May;89(5):597-606 19290006 World J Gastroenterol. 2009 May 7;15(17):2089-96 19418581 Am J Pathol. 2010 Feb;176(2):995-1005 20042682 J Dig Dis. 2010 Feb;11(1):50-4 20132431 BMC Cancer. 2010;10:89 20219106 Nat Cell Biol. 2010 Apr;12(4):390-9 20305651 Clin Cancer Res. 2010 Aug 15;16(16):4289-97 20601442 Leukemia. 2010 Sep;24(9):1555-65 20574452 CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300 20610543 Cell Mol Life Sci. 2010 Oct;67(20):3535-48 20480203 Nature. 2010 Sep 23;467(7314):415-9 20864994 Cell. 2010 Oct 1;143(1):21-6 20887887 J Pathol. 2011 Jan;223(2):102-15 21125669 Oncogene. 2011 Jun 9;30(23):2644-58 21358675 Int J Cancer. 2011 Sep 1;129(5):1064-74 21077158 Nature. 2000 Jun 22;405(6789):974-8 10879542 Apoptosis physiology Carcinoma, Non-Small-Cell Lung metabolism pathology Cell Growth Processes physiology Cell Line, Tumor Cell Movement physiology DNA Methylation Gene Knockdown Techniques Homeodomain Proteins genetics metabolism Humans Lung Neoplasms metabolism pathology MicroRNAs biosynthesis genetics metabolism Neoplasm Invasiveness Up-Regulation PMC3503718 2012 1 18 2012 7 3 2012 8 9 2012 8 11 6 0 2012 8 11 6 0 2013 7 16 6 0 epublish 1471-2407-12-348 10.1186/1471-2407-12-348 22876840 PMC3503718 22869146 2013 06 06 2013 08 05

1476-5594 32 23 2013 Jun 6 Oncogene Epigenetic-induced repression of microRNA-205 is associated with MED1 activation and a poorer prognosis in localized prostate cancer. 2891-9 10.1038/onc.2012.300 Deregulation of microRNA (miRNA) expression can have a critical role in carcinogenesis. Here we show in prostate cancer that miRNA-205 (miR-205) transcription is commonly repressed and the MIR-205 locus is hypermethylated. LOC642587, the MIR-205 host gene of unknown function, is also concordantly inactivated. We show that miR-205 targets mediator 1 (MED1, also called TRAP220 and PPARBP) for transcriptional silencing in normal prostate cells, leading to reduction in MED1 mRNA levels, and in total and active phospho-MED1 protein. Overexpression of miR-205 in prostate cancer cells negatively affects cell viability, consistent with a tumor suppressor function. We found that hypermethylation of the MIR-205 locus was strongly related with a decrease in miR-205 expression and an increase in MED1 expression in primary tumor samples (n=14), when compared with matched normal prostate (n=7). An expanded patient cohort (tumor n=149, matched normal n=30) also showed significant MIR-205 DNA methylation in tumors compared with normal, and MIR-205 hypermethylation is significantly associated with biochemical recurrence (hazard ratio=2.005, 95% confidence interval (1.109, 3.625), P=0.02), in patients with low preoperative prostate specific antigen. In summary, these results suggest that miR-205 is an epigenetically regulated tumor suppressor that targets MED1 and may provide a potential biomarker in prostate cancer management. Hulf T T Epigenetics Group, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. Sibbritt T T Wiklund E D ED Patterson K K Song J Z JZ Stirzaker C C Qu W W Nair S S Horvath L G LG Armstrong N J NJ Kench J G JG Sutherland R L RL Clark S J SJ eng Journal Article Research Support, Non-U.S. Gov't 2012 08 06

England Oncogene 8711562 0950-9232 0 MED1 protein, human 0 MIRN205 microRNA, human 0 Mediator Complex Subunit 1 0 MicroRNAs IM Adenocarcinoma genetics metabolism mortality Aged Base Sequence Cell Line, Tumor Cell Survival DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Gene Silencing Humans Kaplan-Meier Estimate Male Mediator Complex Subunit 1 metabolism MicroRNAs genetics metabolism Middle Aged Molecular Sequence Data Phosphorylation Prognosis Promoter Regions, Genetic Proportional Hazards Models Prostatic Neoplasms genetics metabolism mortality Protein Processing, Post-Translational 2012 8 06 2012 8 8 6 0 2012 8 8 6 0 2013 8 6 6 0 ppublish onc2012300 10.1038/onc.2012.300 22869146 22863767 2012 10 01 2013 06 05 2013 11 15

1367-4811 28 19 2012 Oct 1 Bioinformatics Identifying multi-layer gene regulatory modules from multi-dimensional genomic data. 2458-66 Eukaryotic gene expression (GE) is subjected to precisely coordinated multi-layer controls, across the levels of epigenetic, transcriptional and post-transcriptional regulations. Recently, the emerging multi-dimensional genomic dataset has provided unprecedented opportunities to study the cross-layer regulatory interplay. In these datasets, the same set of samples is profiled on several layers of genomic activities, e.g. copy number variation (CNV), DNA methylation (DM), GE and microRNA expression (ME). However, suitable analysis methods for such data are currently sparse. In this article, we introduced a sparse Multi-Block Partial Least Squares (sMBPLS) regression method to identify multi-dimensional regulatory modules from this new type of data. A multi-dimensional regulatory module contains sets of regulatory factors from different layers that are likely to jointly contribute to a local 'gene expression factory'. We demonstrated the performance of our method on the simulated data as well as on The Cancer Genomic Atlas Ovarian Cancer datasets including the CNV, DM, ME and GE data measured on 230 samples. We showed that majority of identified modules have significant functional and transcriptional enrichment, higher than that observed in modules identified using only a single type of genomic data. Our network analysis of the modules revealed that the CNV, DM and microRNA can have coupled impact on expression of important oncogenes and tumor suppressor genes. The source code implemented by MATLAB is freely available at: http://zhoulab.usc.edu/sMBPLS/. xjzhou@usc.edu Supplementary material are available at Bioinformatics online. Li Wenyuan W Program in Molecular and Computational Biology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. Zhang Shihua S Liu Chun-Chi CC Zhou Xianghong Jasmine XJ eng R01GM074163 GM NIGMS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2012 08 03

England Bioinformatics 9808944 1367-4803 0 MicroRNAs IM Stat Appl Genet Mol Biol. 2009;8:Article28 19572827 Differentiation. 2009 Feb;77(2):162-71 19281776 Int J Cancer. 2009 Nov 1;125(9):2214-8 19621443 PLoS Comput Biol. 2010 Jan;6(1):e1000642 20090830 Cancer Res. 2010 Feb 1;70(3):996-1005 20103632 BMC Bioinformatics. 2010;11:309 20529363 Genome Biol. 2010;11(9):R96 20920250 Mutat Res. 2011 Jun 17;722(2):94-105 20472093 PLoS One. 2011;6(11):e24709 22073136 PLoS Comput Biol. 2011 Nov;7(11):e1002190 22125477 Nat Genet. 2000 May;25(1):25-9 10802651 Oncogene. 2000 May 4;19(19):2324-30 10822383 Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10101-6 10963673 Development. 2002 Jan;129(2):329-37 11807026 Cell. 2002 Feb 22;108(4):439-51 11909516 Nature. 2002 Apr 4;416(6880):499-506 11932736 Bioinformatics. 2002;18 Suppl 1:S136-44 12169541 Cancer Res. 2003 Jan 1;63(1):236-41 12517803 Cancer Res. 2004 Feb 15;64(4):1436-43 14973117 Bioinformatics. 2004 Mar 1;20(4):487-99 14990444 BMC Bioinformatics. 2004 Mar 18;5:31 15113405 Oncogene. 2004 Jun 10;23(27):4745-53 15122336 Oncogene. 2004 Jul 29;23(34):5853-7 15208673 Cell. 1998 May 1;93(3):445-54 9590178 Br J Cancer. 1999 Jun;80(8):1236-44 10376977 RNA. 2005 Mar;11(3):241-7 15701730 Nat Med. 2005 May;11(5):531-7 15821746 Bioinformatics. 2005 Jun;21 Suppl 1:i159-68 15961453 Cancer Res. 2005 Sep 1;65(17):7653-9 16140931 Science. 2005 Sep 2;309(5740):1514-8 16141059 Nat Rev Cancer. 2006 Oct;6(10):813-23 16990858 Nucleic Acids Res. 2007 Jan;35(Database issue):D663-7 17166863 Brief Bioinform. 2007 Jan;8(1):32-44 16772269 Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5959-64 17389406 Bioinformatics. 2007 Jun 15;23(12):1495-502 17483501 Mol Cancer. 2007;6:45 17623056 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18371-6 18003902 Cancer Res. 2008 Jan 15;68(2):425-33 18199536 Clin Cancer Res. 2008 May 1;14(9):2690-5 18451233 Nat Biotechnol. 2008 May;26(5):531-9 18464786 Bioinformatics. 2008 Jul 1;24(13):i156-64 18586709 Mol Carcinog. 2008 Sep;47(9):701-6 18176935 Nature. 2008 Oct 23;455(7216):1061-8 18772890 Stat Appl Genet Mol Biol. 2008;7(1):Article 35 19049491 BMC Syst Biol. 2009;3:65 19558649 Computational Biology methods DNA Copy Number Variations DNA Methylation Female Gene Expression Regulation Gene Regulatory Networks Genomics methods Humans MicroRNAs genetics metabolism Oncogenes Ovarian Neoplasms genetics Regression Analysis PMC3463121 2012 8 3 2012 8 7 6 0 2012 8 7 6 0 2013 6 6 6 0 ppublish bts476 10.1093/bioinformatics/bts476 22863767 PMC3463121 22725689 2013 02 27 2013 08 09

1875-6220 10 1 2013 Mar Curr Drug Discov Technol Past, present and future of nutrigenomics and its influence on drug development. 35-46 The importance of nutrition in disease prevention and treatment has gained much attention with the emergence of next generation sequence technologies allowing full-genome sequencing at reduced cost in weeks rather than months. The vast genetic information needs to be efficiently channeled into a useful format to provide applicability for improved health and treatment of disease. Recently, it also led to the birth of nutrigenomics, which facilitates the investigation of the effects of nutrition on gene expression and beyond. At present, a number of studies have showed the effect of nutrition on gene expression in health and disease. For instance, weight loss and as importantly weight keeping has been demonstrated to be efficiently achieved in obesity treatment through personalized diet planning. Likewise, intensive dietary interventions have showed a significant effect on the expression pattern on cancer-related genes in prostate cancer patients. Epigenetic modifications such as DNA methylation, histone modifications, and microRNA-based gene silencing are strongly affected by nutritional intake. Better understanding of the human genome will further accelerate nutrigenomics applications and the development of nutritional modifications including personalized nutrition for our well-being and will also present a strong influence on future drug discovery. Lundstrom Kenneth K Centre of Kenneth Lundstrcm PanTherapeutics, Rue des Remparts 4, CH1095 Lutry, Switzerland. lundstromkenneth@googlemail.com eng Journal Article Review

United Arab Emirates Curr Drug Discov Technol 101157212 1570-1638 IM Animals Drug Discovery Epigenomics Humans Nutrigenomics 2012 4 10 2012 5 16 2012 6 06 2012 6 26 6 0 2012 6 26 6 0 2013 8 10 6 0 ppublish CDDT-EPUB-20120625-3 22725689 22715154 2012 08 24 2012 10 31

1460-2180 33 9 2012 Sep Carcinogenesis DNA methylation of microRNA genes in multiple myeloma. 1629-38 10.1093/carcin/bgs212 DNA methylation is one of the heritable epigenetic modifications, leading to repressed gene expressions and consequent phenotypic alterations without changing the DNA sequence. MicroRNA (miRNA) is a novel class of short non-coding RNA molecules regulating a wide range of cellular functions through translational repression of their target genes. Recently, epigenetic dysregulation of tumor-suppressor miRNA genes by promoter DNA methylation has been implicated in human cancers, including multiple myeloma (MM). This article presents a brief overview of the pathogenesis of MM, the role of DNA methylation in cancer biology, methods of DNA methylation analysis, miRNA biology and dysregulation of miRNAs in MM and summaries the current data on the role of DNA methylation of tumor-suppressive miRNAs in MM. Wong Kwan Yeung KY Department of Medicine, Queen Mary Hospital, The University of Hong Kong Hong Kong, China. Huang Xiaojun X Chim Chor Sang CS eng Journal Article Research Support, Non-U.S. Gov't Review 2012 06 19

England Carcinogenesis 8008055 0143-3334 0 MicroRNAs IM DNA Methylation Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics Multiple Myeloma etiology genetics pathology Neoplasm Staging 2012 6 19 2012 8 7 2012 6 21 6 0 2012 6 21 6 0 2012 11 1 6 0 ppublish bgs212 10.1093/carcin/bgs212 22715154 22674137 2012 06 07 2012 10 04 2012 11 15

1940-6029 878 2012 Methods Mol. Biol. High-resolution quantitative methylation analysis of microRNA genes using Pyrosequencing™. 229-40 10.1007/978-1-61779-854-2_15 MicroRNA (miRNA) genes have been shown to perform a crucial role in breast cancer metastasis. The epigenetic inactivation of such microRNA genes, as a result of aberrant DNA methylation, is frequently found in human tumours including those of the breast, and this is an area of considerable research activity.Pyrosequencing™ is a new quantitative method for the assessment of DNA methylation, with single CpG site resolution. Pyrosequencing™ can easily be performed in a 96-well-plate format with a cost-effective medium-sized throughput.This chapter provides a general outline of DNA methylation analysis, a detailed protocol of the Pyrosequencing™ procedure, and guidelines for the design of new assays. The strengths and limitations of this approach are discussed throughout the chapter. Lehmann Ulrich U Institute of Pathology, Medizinische Hochschule Hannover, Hannover, Germany. Lehmann.Ulrich@MH-Hannover.de Albat Cord C Kreipe Hans H eng Journal Article

United States Methods Mol Biol 9214969 1064-3745 0 MicroRNAs 0 Sulfites 9007-49-2 DNA OJ9787WBLU hydrogen sulfite IM Base Sequence DNA chemistry genetics isolation & purification DNA Methylation genetics Humans MicroRNAs genetics Molecular Sequence Data Polymerase Chain Reaction Sequence Analysis, DNA methods Sulfites chemistry 2012 6 8 6 0 2012 6 8 6 0 2012 10 5 6 0 ppublish 10.1007/978-1-61779-854-2_15 22674137 22666228 2012 06 05 2012 10 02 2013 08 13

1664-8021 3 2012 Front Genet The epigenetics of renal cell tumors: from biology to biomarkers. 94 10.3389/fgene.2012.00094 Renal cell tumors (RCT) collectively constitute the third most common type of genitourinary neoplasms, only surpassed by prostate and bladder cancer. They comprise a heterogeneous group of neoplasms with distinctive clinical, morphological, and genetic features. Epigenetic alterations are a hallmark of cancer cells and their role in renal tumorigenesis is starting to emerge. Aberrant DNA methylation, altered chromatin remodeling/histone onco-modifications and deregulated microRNA expression not only contribute to the emergence and progression of RCTs, but owing to their ubiquity, they also constitute a promising class of biomarkers tailored for disease detection, diagnosis, assessment of prognosis, and prediction of response to therapy. Moreover, due to their dynamic and reversible properties, those alterations represent a target for epigenetic-directed therapies. In this review, the current knowledge about epigenetic mechanisms and their altered status in RCT is summarized and their envisaged use in a clinical setting is also provided. Henrique Rui R Cancer Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida Porto, Portugal. Luís Ana Sílvia AS Jerónimo Carmen C eng Journal Article 2012 05 30

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1875-5305 20 3 2013 Mar Protein Pept. Lett. MicroRNA mediated network and DNA methylation in colorectal cancer. 352-63 Colorectal cancer (CRC) is one of the most malignant cancers. A growing number of studies have shown that both genetic and epigenetic play important roles in the etiology of CRC. Both microRNA (miRNA) and DNA methylation belong to the scope of epigenetic and there are complex regulatory mechanisms within miRNA and DNA methylation. We compiled 71 CRC related genes and 134 CRC related miRNAs. Then we identified 417 feed forward loops (FFLs) and 37 feedback loops (FBLs) among these genes, miRNAs and transcription factors (TFs). We constructed a network of miRNAs and TFs mediation for CRC utilizing these FFLs and FBLs. Statistical tests proved that these FFLs were significantly enriched in the CRC comparing to the esophageal cancer, breast cancer and randomly selected CRCmiRNA-gene pairs. Analysis of the network singled out 3 core genes, 2 core miRNAs and 5 core TFs. The KEGG enrichment and GO enrichment for the 2 core miRNA target genes indicated that they were significantly enriched in CRC related pathways. (Ex. MARK pathway, TGFβ pathway and cell cycle) Through the investigation on methylation, we found that most of the CRC related genes and miRNAs were prone to be regulated by methylation. This study sheds lights on the regulatory mechanisms in CRC and we provide some insights on the epigenetic of CRC. Li Bi-Qing BQ Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China. Yu Hui H Wang Zhen Z Ding Guo-Hui GH Liu Lei L eng Journal Article

Netherlands Protein Pept Lett 9441434 0929-8665 0 MicroRNAs 0 Transcription Factors IM Colorectal Neoplasms genetics metabolism pathology DNA Methylation genetics Epigenesis, Genetic Gene Expression Regulation, Neoplastic Gene Regulatory Networks Humans Metabolic Networks and Pathways MicroRNAs genetics metabolism Transcription Factors genetics 2011 6 11 2011 9 04 2011 9 05 2012 5 18 6 0 2012 5 18 6 0 2013 9 5 6 0 ppublish PPL-EPUB-20120516-3 22591477 22570537 2012 05 09 2012 08 23 2013 05 29

1176-9351 11 2012 Cancer Inform Integrated Analysis Reveals hsa-miR-142 as a Representative of a Lymphocyte-Specific Gene Expression and Methylation Signature. 61-75 10.4137/CIN.S9037 Gene expression profiling has provided insights into different cancer types and revealed tissue-specific expression signatures. Alterations in microRNA expression contribute to the pathogenesis of many types of human diseases. Few studies have integrated all levels of gene expression, miRNA and methylation to uncover correlations between these data types. We performed an integrated profiling to discover instances of miRNAs associated with a gene expression and DNA methylation signature across multiple cancer types. Using data from The Cancer Genome Atlas (TCGA), we revealed a concordant gene expression and methylation signature associated with the microRNA hsa-miR-142 across the same samples. In all cancer types examined, we found a signature of co-expression of a gene set R and methylated sites M, which correlate positively (M+) or negatively (M-) with the expression of hsa-miR-142. The set R consistently contains many genes, such as TRAF3IP3, NCKAP1L, CD53, LAPTM5, PTPRC, EVI2B, DOCK2, LCP2, CYBB and FYB. The signature is preserved across glioblastoma, ovarian, breast, colon, kidney, lung, uterine and rectum cancer. There is 28% overlap of methylation sites in M between glioblastoma (GBM) and ovarian cancer. There is 60% overlap of genes in R between GBM and ovarian (P = 1.3e(-11)). Most of the genes in R are known to be expressed in lymphocytes and haematopoietic stem cells, while M reflects membrane proteins involved in cell-cell adhesion functions. We speculate that the hsa-miR-142 associated signature may signal haematopoietic-specific processes and an accumulation of methylation events triggering a progressive loss of cell-cell adhesion. We also observed that GBM samples belonging to the proneural subtype tend to have underexpressed hsa-miR-142 and R genes, hypomethylated M+ and hypermethylated M-, while the mesenchymal samples have the opposite profile. Andreopoulos Bill B Center for Computational Biology and Bioinformatics, Department of Electrical Engineering, Columbia University, New York, NY 10027, USA. Anastassiou Dimitris D eng Journal Article 2012 03 12

New Zealand Cancer Inform 101258149 1176-9351 BMC Genomics. 2010;11 Suppl 3:S16 21143783 J Appl Physiol (1985). 2010 Aug;109(2):598-605 20203073 Cancer Cell. 2010 May 18;17(5):510-22 20399149 Nucleic Acids Res. 2010 Jul;38(Web Server issue):W118-23 20529879 PLoS Genet. 2010 Sep;6(9):e1001106 20838592 Cell Res. 2010 Oct;20(10):1158-69 20856265 PLoS One. 2010;5(10):e13696 21060876 Nucleic Acids Res. 2011 Jul;39(12):4984-5002 21378119 Cancer Res. 2011 Jul 1;71(13):4550-61 21555372 Nature. 2011 Jun 30;474(7353):609-15 21720365 Cancer Res. 2011 Sep 1;71(17):5635-45 21737487 Arthritis Rheum. 2011 May;63(5):1376-86 21538319 Leukemia. 2008 May;22(5):1067-71 17972953 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 Neuro Oncol. 2010 Jul;12(7):701-10 20511186 Toxicol Appl Pharmacol. 2011 Feb 15;251(1):70-8 21163286 Nature. 2011 Feb 24;470(7335):548-53 21326202 Mol Med. 2011;17(7-8):726-35 21327300 PLoS One. 2011;6(2):e17490 21364760 Cancer Res. 2011 May 1;71(9):3387-99 21385897 Genes Dev. 2011 Mar 15;25(6):534-55 21406553 Cancer Res. 2011 May 15;71(10):3563-72 21471404 PLoS One. 2011;6(3):e17438 21483847 Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16916-21 12481029 Genome Biol. 2003;4(5):P3 12734009 Cell. 2004 Jan 23;116(2):281-97 14744438 Int Immunol. 2004 Aug;16(8):1109-24 15210650 Biochem Biophys Res Commun. 2004 Sep 17;322(2):403-10 15325244 Nat Genet. 2004 Oct;36(10):1090-8 15448693 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Cancer Cell. 2006 Mar;9(3):157-73 16530701 Nat Rev Cancer. 2006 Apr;6(4):259-69 16557279 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 PLoS Comput Biol. 2007 Mar 9;3(3):e37 17352530 Breast Cancer Res. 2007;9(4):212 17705880 Nat Struct Mol Biol. 2008 Mar;15(3):259-67 18311153 Nature. 2008 Oct 23;455(7216):1061-8 18772890 Cancer Res. 2009 Mar 1;69(5):2091-9 19244127 Clin Cancer Res. 2009 Jun 15;15(12):3927-37 19509173 JAMA. 2009 Jul 15;302(3):261-75 19602686 J Mammary Gland Biol Neoplasia. 2010 Mar;15(1):5-17 20101446 Cancer Cell. 2010 Jan 19;17(1):98-110 20129251 PLoS One. 2011;6(2):e16915 21364938 PMC3306237 cancer correlation gene expression integrated analysis methylation microRNA 2012 3 12 2012 5 10 6 0 2012 5 10 6 0 2012 5 10 6 1 ppublish 10.4137/CIN.S9037 cin-11-2012-061 22570537 PMC3306237 22546179 2012 08 17 2013 01 17 2013 11 06

1756-0500 5 2012 BMC Res Notes Quantitative cross-validation and content analysis of the 450k DNA methylation array from Illumina, Inc. 210 10.1186/1756-0500-5-210 The newly released 450k DNA methylation array from Illumina, Inc. offers the possibility to analyze more than 480,000 individual CpG sites in a user friendly standardized format. In this study the relationship between the β-values provided by the Illumina, Inc. array for each individual CpG dinucleotide and the quantitative methylation levels obtained by pyrosequencing were analyzed. In addition, the representation of microRNA genes and imprinted loci on the Illumina, Inc. array was assessed in detail. Genomic DNA from 4 human breast cancer cell lines (IPH-926, HCC1937, MDA-MB-134, PMC42) and 18 human breast cancer specimens as well as 4 normal mammary epithelial fractions was analyzed on 450k DNA methylation arrays. The β-values for 692 individual CpG sites from 62 different genes were cross-validated using conventional quantitative pyrosequencing. The newly released 450k methylation array from Illumina, Inc. shows a high concordance with quantitative pyrosequencing if identical CpG sites are analyzed in cell lines (Spearman r = 0.88, p ≪ 0.0001), which is somewhat reduced in primary tumor specimens (Spearman r = 0.86, p ≪ 0.0001). 80.7% of the CpG sites show an absolute difference in methylation level of less than 15 percentage points. If different CpG sites in the same CpG islands are targeted the concordance is lower (r = 0.83 in cell lines and r = 0.7 in primary tumors). The number of CpG sites representing microRNA genes and imprinted loci is very heterogeneous (range: 1 - 70 CpG sites for microRNAs and 1 - 288 for imprinted loci). The newly released 450k methylation array from Illumina, Inc. provides a genome-wide quantitative representation of DNA methylation aberrations in a convenient format. Overall, the congruence with pyrosequencing data is very good. However, for individual loci one should be careful to translate the β-values directly into percent methylation levels. Roessler Jessica J Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Str, 1, D-30625, Hannover, Germany. Ammerpohl Ole O Gutwein Jana J Hasemeier Britta B Anwar Sumadi Lukman SL Kreipe Hans H Lehmann Ulrich U eng Journal Article Research Support, Non-U.S. Gov't Validation Studies 2012 04 30

England BMC Res Notes 101462768 1756-0500 0 SNRPN protein, human 0 snRNP Core Proteins IM J Pathol. 2008 Jan;214(1):17-24 17948228 Biotechnol J. 2007 Jan;2(1):41-9 17225249 Nature. 2009 Nov 19;462(7271):315-22 19829295 PLoS One. 2010;5(1):e8888 20126651 Nucleic Acids Res. 2010 Jun;38(11):e125 20371518 Biotechniques. 2010 Apr;48(4):317-9 20569209 Genome Res. 2010 Jul;20(7):883-9 20418490 Nat Biotechnol. 2010 Oct;28(10):1106-14 20852634 Nat Biotechnol. 2010 Oct;28(10):1039-44 20944594 BMC Biotechnol. 2011;11:6 21235780 Nat Rev Genet. 2010 Mar;11(3):191-203 20125086 Epigenetics. 2011 Jun;6(6):692-702 21593595 Genomics. 2011 Oct;98(4):288-95 21839163 Epigenomics. 2011 Dec;3(6):771-84 22126295 Epigenomics. 2009 Dec;1(2):331-45 20526417 Biotechniques. 2003 Jul;35(1):146-50 12866414 Lancet. 1986 Feb 8;1(8476):307-10 2868172 Int J Oncol. 2005 Feb;26(2):499-507 15645136 Nat Rev Genet. 2005 Aug;6(8):597-610 16136652 Nat Genet. 2006 Dec;38(12):1378-85 17072317 Clin Chem. 2007 Jan;53(1):17-23 17095538 J Pathol. 2009 Apr;217(5):620-32 19191266 Base Pairing genetics Breast Neoplasms genetics Cell Line, Tumor DNA Methylation genetics Female Genetic Loci genetics Genomic Imprinting genetics Humans Reproducibility of Results Sequence Analysis, DNA instrumentation methods standards snRNP Core Proteins genetics PMC3420245 2012 2 9 2012 4 30 2012 4 30 2012 5 2 6 0 2012 5 2 6 0 2013 1 18 6 0 epublish 1756-0500-5-210 10.1186/1756-0500-5-210 22546179 PMC3420245 22426647 2012 04 09 2012 08 27 2013 11 21

1791-2431 27 6 2012 Jun Oncol. Rep. microRNA-155 is downregulated in gastric cancer cells and involved in cell metastasis. 1960-6 10.3892/or.2012.1719 microRNA-155 (miR-155), an important multifunctional microRNA, has been implicated in the development of multiple solid tumors, yet, its role in gastric cancer cells has not been fully elucidated. In this study, we find that miR-155 was significantly downregulated in gastric cancer cell lines compared with an immortalized gastric epithelial cell line (GES-1). Overexpression of miR-155 in SGC-7901 and MKN-45 gastric cancer cells dramatically suppressed cell migration, invasion and adhesion in vitro. Overexpression of miR-155 significantly reduced the protein levels of SMAD2 and repressed the activity of a luciferase reporter containing one of the two predicted miR-155 binding sites in SMAD2 3'-UTR, indicating that SMAD2 may be a miR-155 target gene. miR-155 expression was also remarkably restored by a DNA demethylating agent (5-Aza-2-deoxycytidine) in SGC-7901 and MKN-45 gastric cancer cells. Taken together, these data suggest that miR-155 may function as a tumor suppressor to regulate gastric cancer cell metastasis by targeting SMAD2, and its downregulation in gastric cancer cells may be partly ascribed to DNA methylation. Li Cheng-Long CL Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, PR China. Nie Hui H Wang Ming M Su Li-Ping LP Li Jian-Fang JF Yu Ying-Yan YY Yan Min M Qu Qin-Long QL Zhu Zheng-Gang ZG Liu Bing-Ya BY eng Journal Article Research Support, Non-U.S. Gov't 2012 03 13

Greece Oncol Rep 9422756 1021-335X 0 3' Untranslated Regions 0 MIRN155 microRNA, human 0 MicroRNAs 0 SMAD2 protein, human 0 Smad2 Protein 776B62CQ27 decitabine M801H13NRU Azacitidine IM 3' Untranslated Regions Azacitidine analogs & derivatives pharmacology Cell Adhesion Cell Line, Tumor Cell Movement Cell Proliferation DNA Methylation Down-Regulation Gene Expression Regulation, Neoplastic Genes, Tumor Suppressor HEK293 Cells Humans MicroRNAs genetics metabolism Neoplasm Invasiveness Neoplasm Metastasis Smad2 Protein genetics metabolism Stomach Neoplasms genetics metabolism pathology 2011 11 21 2012 2 13 2012 3 13 2012 3 20 6 0 2012 3 20 6 0 2012 8 28 6 0 ppublish 10.3892/or.2012.1719 22426647 22412920 2012 03 13 2012 08 02 2013 11 07

1932-6203 7 3 2012 PLoS ONE Integrated epigenome profiling of repressive histone modifications, DNA methylation and gene expression in normal and malignant urothelial cells. e32750 10.1371/journal.pone.0032750 Epigenetic regulation of gene expression is commonly altered in human cancer. We have observed alterations of DNA methylation and microRNA expression that reflect the biology of bladder cancer. This common disease arises by distinct pathways with low and high-grade differentiation. We hypothesized that epigenetic gene regulation reflects an interaction between histone and DNA modifications, and differences between normal and malignant urothelial cells represent carcinogenic events within bladder cancer. To test this we profiled two repressive histone modifications (H3K9m3 and H3K27m3) using ChIP-Seq, cytosine methylation using MeDIP and mRNA expression in normal and malignant urothelial cell lines. In genes with low expression we identified H3K27m3 and DNA methylation each in 20-30% of genes and both marks in 5% of genes. H3K9m3 was detected in 5-10% of genes but was not associated with overall expression. DNA methylation was more closely related to gene expression in malignant than normal cells. H3K27m3 was the epigenetic mark most specifically correlated to gene silencing. Our data suggest that urothelial carcinogenesis is accompanied by a loss of control of both DNA methylation and H3k27 methylation. From our observations we identified a panel of genes with cancer specific-epigenetic mediated aberrant expression including those with reported carcinogenic functions and members potentially mediating a positive epigenetic feedback loop. Pathway enrichment analysis revealed genes marked by H3K9m3 were involved with cell homeostasis, those marked by H3K27m3 mediated pro-carcinogenic processes and those marked with cytosine methylation were mixed in function. In 150 normal and malignant urothelial samples, our gene panel correctly estimated expression in 65% of its members. Hierarchical clustering revealed that this gene panel stratified samples according to the presence and phenotype of bladder cancer. Dudziec Ewa E Institute for Cancer Studies and Academic Urology Unit, University of Sheffield, Sheffield, United Kingdom. Gogol-Döring Andreas A Cookson Victoria V Chen Wei W Catto James J eng GEO GSE31125 GSE31864 GSE31865 GSE31866 Journal Article Research Support, Non-U.S. Gov't 2012 03 07

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1471-2164 12 Suppl 5 2011 Dec 23 BMC Genomics Functional complementation between transcriptional methylation regulation and post-transcriptional microRNA regulation in the human genome. S15 10.1186/1471-2164-12-S5-S15 DNA methylation in the 5' promoter regions of genes and microRNA (miRNA) regulation at the 3' untranslated regions (UTRs) are two major epigenetic regulation mechanisms in most eukaryotes. Both DNA methylation and miRNA regulation can suppress gene expression and their corresponding protein product; thus, they play critical roles in cellular processes. Although there have been numerous investigations of gene regulation by methylation changes and miRNAs, there is no systematic genome-wide examination of their coordinated effects in any organism. In this study, we investigated the relationship between promoter methylation at the transcription level and miRNA regulation at the post-transcription level by taking advantage of recently released human methylome data and high quality miRNA and other gene annotation data. We found methylation level in the promoter regions and expression level was negatively correlated. Then, we showed that miRNAs tended to target the genes with a low DNA methylation level in their promoter regions. We further demonstrated that this observed pattern was not attributed to the gene expression level, expression broadness, or the number of transcription factor binding sites. Interestingly, we found miRNA target sites were significantly enriched in the genes located in differentially methylated regions or partially methylated domains. Finally, we explored the features of DNA methylation and miRNA regulation in cancer genes and found cancer genes tended to have low methylation level and more miRNA target sites. This is the first genome-wide investigation of the combined regulation of gene expression. Our results supported a complementary regulation between DNA methylation (transcriptional level) and miRNA function (post-transcriptional level) in the human genome. The results were helpful for our understanding of the evolutionary forces towards organisms' complexity beyond traditional sequence level investigation. Su Zhixi Z Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Xia Junfeng J Zhao Zhongming Z eng 50CA95103 CA NCI NIH HHS United States LM009598 LM NLM NIH HHS United States P30-CA68485 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2011 12 23

England BMC Genomics 100965258 1471-2164 0 3' Untranslated Regions 0 MicroRNAs IM Nature. 2004 Jul 22;430(6998):471-6 15269773 Comput Biol Chem. 2011 Jun;35(3):121-5 21666777 Nat Genet. 2005 May;37(5):495-500 15806104 Genes Dev. 2002 Jan 1;16(1):6-21 11782440 Bioinformatics. 2002 Dec;18(12):1585-92 12490442 Nat Genet. 2003 Mar;33 Suppl:245-54 12610534 Trends Genet. 2003 Jul;19(7):362-5 12850439 Dev Biol. 2003 Aug 15;260(2):404-13 12921741 Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7 15075390 Nature. 2004 May 27;429(6990):457-63 15164071 Nature. 2005 Mar 17;434(7031):338-45 15735639 FEBS Lett. 2005 Mar 21;579(8):1795-801 15763554 PLoS Med. 2005 Jun;2(6):e161 15971941 Genomics. 2005 Aug;86(2):127-41 15950434 Nat Rev Genet. 2005 Aug;6(8):597-610 16136652 Mol Biol Evol. 2005 Oct;22(10):2113-8 15987875 Stem Cells. 2005 Oct;23(9):1343-56 16081666 Cell. 2005 Dec 16;123(6):1133-46 16337999 Cancer Res. 2006 Jan 1;66(1):290-302 16397242 Biochem Pharmacol. 2004 Sep 15;68(6):1187-97 15313416 J Mol Evol. 1980 Dec;16(2):111-20 7463489 Nucleic Acids Res. 1994 Nov 11;22(22):4673-80 7984417 Mol Cell Biol. 1999 Jan;19(1):164-72 9858541 Genes Dev. 1999 Jan 1;13(1):26-34 9887097 Cancer Res. 2006 Jan 15;66(2):820-7 16424014 Nat Genet. 2006 Jun;38 Suppl:S8-13 16736023 Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14027-32 16968779 Biochem Biophys Res Commun. 2007 Jan 19;352(3):733-8 17141185 Genome Res. 2007 Jan;17(1):16-22 17095709 Nat Genet. 2007 Apr;39(4):457-66 17334365 Proc Natl Acad Sci U S A. 2007 May 15;104(20):8346-51 17483452 Mol Biol Evol. 2007 Sep;24(9):1991-2000 17591602 Genetica. 2007 Oct;131(2):151-6 17160620 Annu Rev Cell Dev Biol. 2007;23:175-205 17506695 Cell Mol Life Sci. 2007 Oct;64(19-20):2522-4 17712527 Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8 17991681 Nat Rev Genet. 2008 Feb;9(2):102-14 18197166 Bioinformatics. 2008 Feb 1;24(3):325-32 18048393 Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2946-50 18287013 Genome Biol. 2008;9(5):R79 18477403 PLoS One. 2008;3(10):e3380 18846217 J Exp Zool B Mol Dev Evol. 2009 May 15;312B(3):164-70 19214983 Biochem Biophys Res Commun. 2009 May 15;382(4):643-5 19302978 Proc Natl Acad Sci U S A. 2009 May 12;106(19):7915-20 19416898 Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11206-11 19556545 Genomics. 2009 Aug;94(2):117-24 19409480 Biol Reprod. 2009 Aug;81(2):438-43 19369649 BMC Genomics. 2009;10:431 19751524 Nature. 2009 Nov 19;462(7271):315-22 19829295 Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21672-7 20018717 PLoS Genet. 2010 Sep;6(9):e1001134 20885785 Genome Res. 2010 Nov;20(11):1503-11 20686123 PLoS Biol. 2010;8(11):e1000533 21085693 BMC Genomics. 2010;11 Suppl 3:S5 21143787 Nucleic Acids Res. 2011 Jan;39(Database issue):D152-7 21037258 Epigenetics. 2011 Feb;6(2):134-40 20962593 Nature. 2011 Mar 3;471(7336):68-73 21289626 Genes Dev. 2011 May 15;25(10):1010-22 21576262 Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R3-R10 15809270 3' Untranslated Regions Animals CpG Islands DNA Methylation Databases, Genetic Epigenesis, Genetic Genome, Human Humans Mice MicroRNAs metabolism Promoter Regions, Genetic PMC3287497 2011 12 23 2012 2 29 6 0 2012 3 6 6 0 2012 6 19 6 0 ppublish 1471-2164-12-S5-S15 10.1186/1471-2164-12-S5-S15 22369656 PMC3287497 22359293 2012 02 23 2012 06 25 2013 11 21

1940-6029 863 2012 Methods Mol. Biol. Epigenetics of colon cancer. 177-85 10.1007/978-1-61779-612-8_10 Accumulation of genetic and epigenetic alterations transforms normal colonic epithelial cells to adenocarcinoma cells. Genetic alterations include mutations in tumor suppressor genes and oncogenes, whereas epigenetic mechanisms are defined as heritable alterations in gene expression that is independent of changes in the primary DNA sequence. Role of epigenetic mechanisms in development and maintenance of organ- and tissue-specific gene expression is now realized. Disturbances in epigenetic landscape can lead to malignant cellular makeover, and these heritable changes are maintained through various cycles of cell division that renders cells to have discrete identity with similar genetic information. Epigenetic alterations in colorectal cancer (CRC) that transform colonic epithelial cells into adenocarcinoma cells include aberrant DNA methylation, chromatin modifications, and noncoding RNAs, especially microRNA expression. CpG island DNA methylation and aberrant methylation of genes drive the initiation and progression of CRC. Histone modifications impinge on chromatin structure and gene expression and thus play an important role in gene silencing in CRC. DNA hypermethylation also leads to downregulation and inappropriate expression of certain microRNAs that act like tumor suppressor genes. Determining the causes and roles of epigenetic instability in CRC pathogenesis will lead to effective prevention and therapeutic strategies for patients with CRC. Epigenetic drugs that underscore the reversible nature of epigenetic events have led the possibility of epigenetic therapy as a treatment option in CRC. Khare Sharad S Hines Veterans Affairs Medical Center, Hines, IL, USA. skhare@lumc.edu Verma Mukesh M eng Journal Article Review

United States Methods Mol Biol 9214969 1064-3745 0 Histones 0 MicroRNAs 935E97BOY8 Folic Acid IM Adenocarcinoma genetics metabolism Colonic Neoplasms genetics metabolism CpG Islands genetics DNA Methylation Epigenesis, Genetic Folic Acid blood Histones metabolism Humans MicroRNAs genetics metabolism Risk Factors 2012 2 24 6 0 2012 2 24 6 0 2012 6 26 6 0 ppublish 10.1007/978-1-61779-612-8_10 22359293 22332092 2012 02 14 2012 06 18 2014 03 19

2156-5376 2 6 2011 Nov Adv Nutr Dietary factors and epigenetic regulation for prostate cancer prevention. 497-510 10.3945/an.111.001032 The role of epigenetic alterations in various human chronic diseases has gained increasing attention and has resulted in a paradigm shift in our understanding of disease susceptibility. In the field of cancer research, e.g., genetic abnormalities/mutations historically were viewed as primary underlying causes; however, epigenetic mechanisms that alter gene expression without affecting DNA sequence are now recognized as being of equal or greater importance for oncogenesis. Methylation of DNA, modification of histones, and interfering microRNA (miRNA) collectively represent a cadre of epigenetic elements dysregulated in cancer. Targeting the epigenome with compounds that modulate DNA methylation, histone marks, and miRNA profiles represents an evolving strategy for cancer chemoprevention, and these approaches are starting to show promise in human clinical trials. Essential micronutrients such as folate, vitamin B-12, selenium, and zinc as well as the dietary phytochemicals sulforaphane, tea polyphenols, curcumin, and allyl sulfur compounds are among a growing list of agents that affect epigenetic events as novel mechanisms of chemoprevention. To illustrate these concepts, the current review highlights the interactions among nutrients, epigenetics, and prostate cancer susceptibility. In particular, we focus on epigenetic dysregulation and the impact of specific nutrients and food components on DNA methylation and histone modifications that can alter gene expression and influence prostate cancer progression. Ho Emily E Linus Pauling Institute, Department of Nutrition and Exercise Sciences, Oregon State University, Corvallis, OR, USA. emily.ho@oregonstate.edu. Beaver Laura M LM Williams David E DE Dashwood Roderick H RH eng CA122906 CA NCI NIH HHS United States CA122959 CA NCI NIH HHS United States CA65525 CA NCI NIH HHS United States CA80176 CA NCI NIH HHS United States CA90890 CA NCI NIH HHS United States P01 CA090890 CA NCI NIH HHS United States P30 ES00210 ES NIEHS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Review 2011 11 03

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2005 May;26(5):603-9 15842781 Biochem Pharmacol. 2005 May 15;69(10):1523-31 15857617 Nature. 2005 Jun 30;435(7046):1262-6 15988529 Mol Cell. 2005 Aug 5;19(3):381-91 16061184 Genome Biol. 2005;6(8):227 16086857 Nature. 2005 Sep 15;437(7057):436-9 16079795 Int J Cancer. 2005 Nov 20;117(4):667-9 15945102 DNA Methylation drug effects genetics Epigenesis, Genetic Food Histones drug effects Humans Male MicroRNAs drug effects Micronutrients pharmacology Plant Extracts pharmacology Prostatic Neoplasms genetics prevention & control Trace Elements pharmacology PMC3226387 2011 11 3 2012 2 15 6 0 2012 2 15 6 0 2012 6 19 6 0 ppublish 10.3945/an.111.001032 001032 22332092 PMC3226387 22323555 2012 03 29 2012 05 11

1465-3621 42 4 2012 Apr Jpn. J. Clin. Oncol. Recent progress in carcinogenesis, progression and management of upper GI cancer: the 21st Hiroshima Cancer Seminar--the 5th Three Universities' Consortium International Symposium, 6 November 2011, International Conference Center Hiroshima. 351-6 10.1093/jjco/hys008 The 21st Hiroshima Cancer Seminar focused on recent progress of carcinogenesis, progression and management of upper gastrointestinal cancers. β-Catenin and p120 mediate peroxisome proliferator-activated receptor δ-dependent proliferation induced by Helicobacter pylori in gastric epithelia. Helicobacter pylori CagA plays an important role in stomach carcinogenesis via altered signal transduction and cell polarity by interactions with several host proteins. Inflammation caused by H. pylori infection is responsible for inducing aberrant DNA methylation. The gastric gland mucin-specific αGlcNAc plays dual roles in preventing gastric cancer, inhibition of H. pylori infection and suppression of tumor-promoting inflammation. Information obtained from transcriptome dissection greatly contributes to understanding the molecular character of each mucin phenotype of gastric cancer. The standardized biomarkers will serve as good predictive and prognostic markers for gastric cancer. A microRNA expression profile may be useful for the diagnosis of gastric cancer. Bone marrow-derived mesenchymal stem cells may provide an advantageous microenvironment for re-acquisition of stemness of gastric cancer cells. Recent progress in molecular biology research has enabled the clinical development of molecular targeting agents for gastric cancer, such as trastuzumab. The target molecule-based inhibition of the stromal reaction in the microenvironment may hold promise as an effective anti-tumor therapy. Since robotic surgery is feasible and safe, and provides adequate and precise lymph node dissection, it may be one of the good options for gastric cancer in the near future. Yasui Wataru W Hiroshima Cancer Seminar Foundation, 3-8-6 Sendamachi, Naka-ku, Hiroshima 730-0052, Japan. Ito Hisao H Peek Richard R Jr Tahara Eiichi E eng Congresses 2012 02 09

England Jpn J Clin Oncol 0313225 0368-2811 0 Antigens, Bacterial 0 Bacterial Proteins 0 cagA protein, Helicobacter pylori IM Antigens, Bacterial physiology Bacterial Proteins physiology Cell Transformation, Neoplastic genetics pathology Disease Progression Gastrointestinal Neoplasms genetics microbiology pathology therapy Helicobacter Infections complications Helicobacter pylori metabolism Humans Stomach Neoplasms 2012 2 9 2012 2 11 6 0 2012 2 11 6 0 2012 5 12 6 0 ppublish hys008 10.1093/jjco/hys008 22323555 22303362 2012 02 03 2012 10 02 2013 08 13

1664-8021 2 2011 Front Genet Epigenomics of ovarian cancer and its chemoprevention. 67 10.3389/fgene.2011.00067 Ovarian cancer is a major cause of death among gynecological cancers and its etiology is still unclear. Currently, the two principle obstacles in treating this life threatening disease are lack of effective biomarkers for early detection and drug resistance after initial chemotherapy. Similar to other cancers, the initiation and development of ovarian cancer is characterized by disruption of oncogenes and tumor suppressor genes by both genetic and epigenetic mechanisms. While it is well known that it is challenging to treat ovarian cancer through a genetic strategy due in part to its heterogeneity, the reversibility of epigenetic mechanisms involved in ovarian cancer opens exciting new avenues for treatment. The epigenomics of ovarian cancer has therefore become a rapidly expanding field leading to intense investigation. A review on the current status of the field is thus warranted. In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies. Chen Huaping H Department of Biology, University of Alabama at Birmingham Birmingham, AL, USA. Hardy Tabitha M TM Tollefsbol Trygve O TO eng Journal Article 2011 10 04

Switzerland Front Genet 101560621 1664-8021 PMC3268620 biomarkers chemoprevention epigenomics ovarian cancer 2011 7 30 2011 9 13 2011 10 04 2012 2 4 6 0 2012 2 4 6 0 2012 2 4 6 1 epublish 10.3389/fgene.2011.00067 22303362 PMC3268620 22299205 2012 02 03 2012 02 21

0126-8635 33 2 2011 Dec Malays J Pathol Epigenetics in disease and cancer. 61-70 Since the discovery of the double-helical structure of DNA, genetic regulation of gene expression has been well elucidated. More recently, another equally, if not more, important scheme of regulation of gene expression, called epigenetics, has emerged to explain the many biological observations that traditional genetic mechanisms have failed to decipher. Epigenetics is a discipline of study on the biological consequences of cellular alterations that do not involve nucleotide changes, as opposed to genetic mutations. Epigenetic changes are reversible and may lead to loss or gain of biological functions. The three most reported mechanisms of epigenetic regulation of gene expression involve changes in: (i) chromatin remodelling, (ii) DNA methylation and (iii) microRNA (miRNA). More importantly, many of the elucidated epigenetic changes are linked to the pathogenesis of human diseases and cancers. In this mini review, core concepts and basic experimental approaches in the study of epigenetic regulation of gene expression are briefly reviewed in relation to disease, with emphasis on cancer. This mini review also intends to highlight the fact that, besides genetics, epigenetics is now a discipline physicians and clinical research scientists can no longer ignore in their pursuit to understand disease and cancer and to develop new therapeutic strategies for treatment. Choo Kong-Bung KB Faculty of Medicine and Health Sciences, University Tunku Abdul Rahman, Selangor, Malaysia. chookb@utar.edu.my eng Journal Article Review

Malaysia Malays J Pathol 8101177 0126-8635 IM Animals Epigenesis, Genetic Humans Neoplasms genetics 2012 2 4 6 0 2012 2 4 6 0 2012 2 22 6 0 ppublish 22299205 22277129 2012 03 09 2012 06 25 2013 10 14

1471-2407 12 2012 BMC Cancer Disruption of CTCF at the miR-125b1 locus in gynecological cancers. 40 10.1186/1471-2407-12-40 In cancer cells, transcriptional gene silencing has been associated with genetic and epigenetic defects. The disruption of DNA methylation patterns and covalent histone marks has been associated with cancer development. Until recently, microRNA (miRNA) gene silencing was not well understood. In particular, miR-125b1 has been suggested to be an miRNA with tumor suppressor activity, and it has been shown to be deregulated in various human cancers. In the present study, we evaluated the DNA methylation at the CpG island proximal to the transcription start site of miR-125b1 in cancer cell lines as well as in normal tissues and gynecological tumor samples. In addition, we analyzed the association of CTCF and covalent histone modifications at the miR-125b1 locus. To assess the DNA methylation status of the miR-125b1, genomic DNA was transformed with sodium bisulfite, and then PCR-amplified with modified primers and sequenced. The miR-125b1 gene expression was analyzed by qRT-PCR using U6 as a control for constitutive gene expression. CTCF repressive histone marks abundance was evaluated by chromatin immunoprecipitation assays. The disruption of CTCF in breast cancer cells correlated with the incorporation of repressive histone marks such H3K9me3 and H3K27me3 as well as with aberrant DNA methylation patterns. To determine the effect of DNA methylation at the CpG island of miR-125b1 on the expression of this gene, we performed a qRT-PCR assay. We observed a significant reduction on the expression of miR-125b1 in cancer cells in comparison with controls, suggesting that DNA methylation at the CpG island might reduce miR-125b1 expression. These effects were observed in other gynecological cancers, including ovarian and cervical tumors. A reduction of miR-125b1 expression in cancers, correlated with methylation, repressive histone marks and loss of CTCF binding at the promoter region. Soto-Reyes Ernesto E Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología (INCan), Universidad Nacional Autónoma de México (UNAM), México, DF, México. González-Barrios Rodrigo R Cisneros-Soberanis Fernanda F Herrera-Goepfert Roberto R Pérez Víctor V Cantú David D Prada Diddier D Castro Clementina C Recillas-Targa Félix F Herrera Luis A LA eng Journal Article Research Support, Non-U.S. Gov't 2012 01 25

England BMC Cancer 100967800 1471-2407 0 CCCTC-binding factor 0 DNA, Neoplasm 0 Histones 0 MIRN125 microRNA, human 0 MicroRNAs 0 Repressor Proteins IM Genes Dev. 2004 Jul 1;18(13):1592-605 15231737 Cancer. 2012 Jan 1;118(1):232-40 21713760 J Cell Mol Med. 2006 Jul-Sep;10(3):554-68 16989720 J Biol Chem. 2007 Jan 12;282(2):1479-86 17110380 Eur J Cancer. 2007 Jan;43(1):210-9 17071074 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Cancer Res. 2007 Mar 15;67(6):2577-85 17363576 Cell. 2007 May 18;129(4):823-37 17512414 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 J Pathol. 2008 Jan;214(1):17-24 17948228 Cell Cycle. 2008 Mar 1;7(5):570-2 18256538 Cell Cycle. 2008 Aug 15;7(16):2485-92 18719380 Curr Pharm Des. 2008;14(28):2999-3019 18991715 Am J Pathol. 2009 Apr;174(4):1131-8 19264914 Mol Cell. 2009 May 15;34(3):271-84 19450526 Cell. 2009 Jun 26;137(7):1194-211 19563753 Oncogene. 2010 Apr 15;29(15):2217-27 20101205 PLoS One. 2010;5(6):e11166 20567512 J Biol Chem. 2010 Jul 9;285(28):21496-507 20460378 Cancer Metastasis Rev. 2010 Dec;29(4):785-99 20938719 Cancer Res. 2010 Nov 15;70(22):9175-84 20978187 Cell. 2011 Mar 4;144(5):646-74 21376230 FEBS J. 2011 May;278(10):1598-609 21395977 Cancer Res. 2011 May 15;71(10):3552-62 21444677 Nat Genet. 2011 Jul;43(7):630-8 21685913 Nat Genet. 2011 Jul;43(7):615-6 21709679 FEBS Lett. 2011 Jul 7;585(13):2087-99 20708002 Biochem Cell Biol. 2011 Oct;89(5):479-88 21846316 Int J Cancer. 2004 Sep 20;111(5):669-78 15252835 Breast Neoplasms genetics metabolism Cell Line, Tumor CpG Islands genetics DNA Methylation genetics DNA, Neoplasm genetics Epigenesis, Genetic genetics Female Gene Silencing Histones metabolism Humans MicroRNAs genetics Ovarian Neoplasms genetics metabolism Repressor Proteins genetics Uterine Cervical Neoplasms genetics metabolism PMC3297514 2011 9 26 2012 1 25 2012 1 25 2012 1 27 6 0 2012 1 27 6 0 2012 6 26 6 0 epublish 1471-2407-12-40 10.1186/1471-2407-12-40 22277129 PMC3297514 22263639 2012 03 14 2013 06 20

1399-0004 81 4 2012 Apr Clin. Genet. Epigenetics of colorectal cancer. 312-8 10.1111/j.1399-0004.2011.01829.x Colorectal cancer (CRC) develops through a multistep process that results from the progressive accumulation of mutations and epigenetic alterations in tumor suppressor genes and oncogenes. Epigenetic modifications, that have a fundamental role in the regulation of gene expression, involve DNA methylation, specific histone modifications and non-coding RNAs (ncRNAs) interventions. Many genes have been until now studied to detect their methylation status during CRC carcinogenesis; and the functions of many of these genes in cancer initiation and progression are being clarified. Less is known about the patterns of histone modification alterations in CRC. Epigenetic deregulation of the ncRNAs or the genes involved in their biogenesis have been described in tumor progression and some examples of dysregulated microRNA were found also in CRC cells. Diet has an important role in the etiology of colon cancer. Folate is involved via 5-methyltetrahydrofolate in the conversion of homocysteine to methionine, which is then used to form the main DNA methylating agent S-adenosylmethionine. However, the role of folate in protecting from or in promoting CRC, depending on conditions, is still debated. The study of epigenetic marks to better characterize CRC and to identify new tools for diagnosis and prognosis as well as for therapeutic interventions is extremely promising. © 2012 John Wiley & Sons A/S. Migheli F F Department of Surgery Department of Human and Environmental Sciences, University of Pisa, Via S. Giuseppe 22, Pisa, Italy. Migliore L L eng Journal Article Review 2012 01 20

Denmark Clin Genet 0253664 0009-9163 0 Histones IM Animals Colorectal Neoplasms diagnosis genetics pathology DNA Methylation Epigenesis, Genetic Histones metabolism Humans Prognosis 2012 1 20 2012 1 24 6 0 2012 1 24 6 0 2013 6 21 6 0 ppublish 10.1111/j.1399-0004.2011.01829.x 22263639 22219034 2012 03 07 2012 04 30

1423-0380 33 2 2012 Apr Tumour Biol. Emerging links between epigenetic alterations and dysregulation of noncoding RNAs in cancer. 277-85 10.1007/s13277-011-0308-9 Epigenetic changes, including DNA methylation and histone modification, play key roles in the dysregulation of tumor-related genes, thereby affecting numerous cellular processes, including cell proliferation, cell adhesion, apoptosis, and metastasis. In recent years, numerous studies have shown that noncoding RNAs (ncRNAs) are key players in the initiation and progression of cancer and epigenetic mechanisms are deeply involved in their dysregulation. Indeed, the growing list of microRNA (miRNA) genes aberrantly methylated in cancer suggests that a large number of miRNAs exert tumor-suppressive or oncogenic effects. In addition, it now appears that long ncRNAs may be causally related to epigenetic dysregulation of critical genes in cancer. Dissection of the relationships between ncRNAs and epigenetic alterations may lead to the development of novel approaches to the diagnosis and treatment of cancer. Maruyama Reo R Department of Molecular Biology, Sapporo Medical University, S1, W17, Chuo-Ku, Sapporo, 060-8556, Japan. Suzuki Hiromu H Yamamoto Eiichiro E Imai Kohzoh K Shinomura Yasuhisa Y eng Journal Article Review 2012 01 05

Netherlands Tumour Biol 8409922 1010-4283 0 Chromatin 0 Histones 0 MicroRNAs 0 RNA, Untranslated 0 Tumor Markers, Biological 63231-63-0 RNA IM Animals Apoptosis Chromatin metabolism DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Histones chemistry Humans MicroRNAs metabolism Neoplasms metabolism RNA metabolism RNA, Untranslated metabolism Tumor Markers, Biological metabolism 2011 11 26 2011 12 21 2012 1 5 2012 1 6 6 0 2012 1 6 6 0 2012 5 1 6 0 ppublish 10.1007/s13277-011-0308-9 22219034 22167392 2012 10 11 2013 07 26

1559-131X 29 4 2012 Dec Med. Oncol. MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer. 2701-9 10.1007/s12032-011-0134-3 Studies have shown that microRNA-148a (miR-148a) was proved to be silenced while DNA methyltransferase 1 (DNMT1) was over-expressed in gastric cancer. But the mechanism of aberrant expression of miR-148a and DNMT1 and their relationships in gastric cancer are still unknown. The aims of this study were to investigate the expression profile of miR-148a and DNMT1 and reveal whether they have any relationships. We used reverse-transcriptase quantitative real-time PCR, methylation-specific PCR and Western blot to measure the level of miR-148a expression, DNA methylation level and DNMT1 expression, respectively. Gastric cancer cells were transfected with plasmid or siRNA or treated with 5-aza-2'-deoxycytidine. Cell proliferation and apoptosis were detected by cell counting and flow cytometric analysis. In this study, we demonstrated that gastric cancer tissues and cell lines displayed a consistent down-regulation of miR-148a and hypermethylation of promoter region. DNMT1 was over-expressed in primary tumors and cell lines, while knockdown of DNMT1 using siRNA could decrease methylation level of miR-148a promoter and restore its expression. Furthermore, ectopic over-expression of miR-148a in cancer cell lines caused reduction in DNMT1 expression and inhibited cell proliferation, but no obvious change was found in apoptosis rate. These results suggest that miR-148a is inactivated by DNA hypermethylation of promoter region in gastric cancer, which is mediated through DNMT1 over-expression. Additionally, the silence of miR-148a reduces its suppression to DNMT1 in gastric cancer, and this may in turn result in over-expression of DNMT1 and promote DNA hypermethylation. Zhu Akao A Department of General Surgery, Nanjing Medical University Affiliated Wuxi Second Hospital, No. 68, ZhongShan Road of Wuxi City, Wuxi, 214002, JiangSu Province, People's Republic of China. Xia Jiazeng J Zuo Junbo J Jin Shimao S Zhou Hong H Yao Lubin L Huang Hongyu H Han Zhijun Z eng Journal Article Research Support, Non-U.S. Gov't 2011 12 14

United States Med Oncol 9435512 1357-0560 0 MIRN148 microRNA, human 0 MicroRNAs EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 IM Cell Line, Tumor Cell Proliferation CpG Islands DNA (Cytosine-5-)-Methyltransferase physiology DNA Methylation Humans MicroRNAs genetics Promoter Regions, Genetic Stomach Neoplasms genetics pathology 2011 11 22 2011 12 2 2011 12 14 2011 12 15 6 0 2011 12 15 6 0 2013 7 28 6 0 ppublish 10.1007/s12032-011-0134-3 22167392 22161696 2012 01 09 2012 07 03

1559-0267 42 1 2012 Feb Clin Rev Allergy Immunol The therapeutic potential of epigenetics in autoimmune diseases. 92-101 10.1007/s12016-011-8293-8 Autoimmune diseases now include over 100 conditions and are estimated to affect over 20 million people in the United States or 5% of the world population with numerous geographical differences coined as geoepidemiology. Further, concordance rates in monozygotic twins are significantly higher compared to dizygotic sets while being significantly below 50% for most autoimmune diseases. These lines of evidence suggest that additional mechanisms are needed to link the individual susceptibility with the proposed chemical and infectious factors in the environment. Epigenetics may well constitute this missing link to include DNA methylation, histone changes, and microRNA which contribute to the epigenome characterizing specific diseases. Importantly, these epigenetic changes may be ideal targets for new personalized treatments as suggested by data in cancer. A number of chemical and physical factors, along with proposed infectious agents or aging, are involved in the etiopathogenesis of autoimmune diseases through epigenetic changes. The most prominent evidence on the association between environment and autoimmunity has been reported in systemic lupus erythematosus, but similar mechanisms were proposed in rheumatoid arthritis, systemic sclerosis, and type 1 diabetes. De Santis Maria M Autoimmunity and Metabolism Unit, IRCCS Istituto Clinico Humanitas, Rozzano, Italy. Selmi Carlo C eng Journal Article Review

United States Clin Rev Allergy Immunol 9504368 1080-0549 IM Animals Autoimmune Diseases etiology genetics immunology Disease Susceptibility Environment Epigenomics methods Humans 2011 12 14 6 0 2011 12 14 6 0 2012 7 4 6 0 ppublish 10.1007/s12016-011-8293-8 22161696 22140553 2011 12 05 2012 04 09 2013 10 15

1932-6203 6 11 2011 PLoS ONE A systematic analysis on DNA methylation and the expression of both mRNA and microRNA in bladder cancer. e28223 10.1371/journal.pone.0028223 DNA methylation aberration and microRNA (miRNA) deregulation have been observed in many types of cancers. A systematic study of methylome and transcriptome in bladder urothelial carcinoma has never been reported. The DNA methylation was profiled by modified methylation-specific digital karyotyping (MMSDK) and the expression of mRNAs and miRNAs was analyzed by digital gene expression (DGE) sequencing in tumors and matched normal adjacent tissues obtained from 9 bladder urothelial carcinoma patients. We found that a set of significantly enriched pathways disrupted in bladder urothelial carcinoma primarily related to "neurogenesis" and "cell differentiation" by integrated analysis of -omics data. Furthermore, we identified an intriguing collection of cancer-related genes that were deregulated at the levels of DNA methylation and mRNA expression, and we validated several of these genes (HIC1, SLIT2, RASAL1, and KRT17) by Bisulfite Sequencing PCR and Reverse Transcription qPCR in a panel of 33 bladder cancer samples. We characterized the profiles between methylome and transcriptome in bladder urothelial carcinoma, identified a set of significantly enriched key pathways, and screened four aberrantly methylated and expressed genes. Conclusively, our findings shed light on a new avenue for basic bladder cancer research. Zhu Jialou J Beijing Genomics Institute at Shenzhen, Shenzhen, China. Jiang Zhimao Z Gao Fei F Hu Xueda X Zhou Liang L Chen Jiahao J Luo Huijuan H Sun Jihua J Wu Song S Han Yonghua Y Yin Guangliang G Chen Maoshan M Han Zujing Z Li Xianxin X Huang Yi Y Zhang Weixing W Zhou Fangjian F Chen Tong T Fa Pingping P Wang Yong Y Sun Liang L Leng Huimin H Sun Fenghao F Liu Yuchen Y Ye Mingzhi M Yang Huanming H Cai Zhiming Z Gui Yaoting Y Zhang Xiuqing X eng Journal Article Research Support, Non-U.S. Gov't 2011 11 30

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1879-0593 48 1 2012 Jan Oral Oncol. Methylation of microRNA-9 is a specific and sensitive biomarker for oral and oropharyngeal squamous cell carcinomas. 73-8 10.1016/j.oraloncology.2011.11.006 Detection of DNA methylation has produced promising results as biomarkers for head and neck squamous cell carcinoma (HNSCC). However, current panels are limited by an insufficient number of sensitive and specific tumor markers. MicroRNAs (miR) play an important role in tumorigenesis, and may represent a novel panel of molecules for the development of cancer biomarkers. We investigated methylation of three miRNA promoter sites of miR-9 (miR-9-1, miR-9-2, miR-9-3) in 107 human head and neck tissue samples and controls. We found methylations of miR-9-1 and miR-9-3 were higher in oral and oropharyngeal carcinomas than that in laryngeal carcinoma, achieving a combined sensitivity of 63% and 56%, respectively, for these two tumor types, compared to 21% for the laryngeal carcinoma. Quantitative PCR of miR-9 showed reduced expression associated with methylation of miR-9 in tumor tissues. To investigate the functional consequences of miR-9 methylation, we found that miR-9 methylation is correlated with miR-9 expression level in human HNSCC cell lines. Demethylation treatment using 5-aza-deoxycytidine restored its expression in a miR-9 methylated human HNSCC cell line UM-SCC22A. Furthermore, cell proliferation and viability was significantly inhibited, while PTEN expression was elevated after transfection of miR-9 into the UM-SCC22A cell line. In summary, our results suggest that methylations of miR-9-1 and miR-9-3 are sensitive and specific biomarkers for HNSCC, particularly for oral and oropharyngeal squamous cell carcinomas. In addition, miR-9 may function as a tumor suppressor in HNSCC through inhibition of cell proliferation and elevation of tumor suppressor PTEN. Copyright © 2011 Elsevier Ltd. All rights reserved. Minor Jacob J Department of Otolaryngology, University of Colorado Denver, Aurora, CO, USA. Wang Xiaotian X Zhang Fang F Song John J Jimeno Antonio A Wang Xiao-Jing XJ Lu Xian X Gross Neil N Kulesz-Martin Molly M Wang Daren D Lu Shi-Long SL eng R01 DE021788 DE NIDCR NIH HHS United States R01 DE021788-01 DE NIDCR NIH HHS United States R01 DE021788-02 DE NIDCR NIH HHS United States Journal Article Research Support, Non-U.S. Gov't 2011 11 30

England Oral Oncol 9709118 1368-8375 0 MIRN9 microRNA, human 0 MicroRNAs 0 Tumor Markers, Biological IM Lancet Oncol. 2006 Jan;7(1):77-82 16389187 Cancer Cell. 2004 Apr;5(4):311-6 15093538 Clin Cancer Res. 2008 Jan 1;14(1):97-107 18172258 Cancer Res. 2008 Apr 1;68(7):2094-105 18381414 Mol Cancer. 2008;7:35 18442408 Cancer Biol Ther. 2008 Jul;7(7):1146-56 18535405 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Int J Cancer. 2009 Feb 1;124(3):568-77 18973228 Brain Pathol. 2009 Jul;19(3):375-83 18624795 J Exp Clin Cancer Res. 2009;28:82 19531230 CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49 19474385 Cancer Res. 2009 Jul 15;69(14):5936-45 19549897 FEBS J. 2009 Oct;276(19):5537-46 19702828 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 Breast Cancer Res Treat. 2009 Nov;118(1):185-96 18777135 J Clin Oncol. 2009 Dec 1;27(34):5848-56 19884536 Cancer Res. 2010 Jan 1;70(1):367-77 20028871 Cancer Res. 2010 Feb 15;70(4):1441-8 20124485 Cancer Metastasis Rev. 2010 Mar;29(1):181-206 20135198 Nat Cell Biol. 2010 Mar;12(3):247-56 20173740 Mol Cancer. 2010;9:16 20102618 Carcinogenesis. 2010 May;31(5):864-70 20197299 Head Neck. 2010 Aug;32(8):1099-111 20213828 Oncogene. 2010 Oct 21;29(42):5724-8 20676129 Biochim Biophys Acta. 2010 Oct-Dec;1799(10-12):694-701 20493980 Nat Rev Cancer. 2011 Jan;11(1):9-22 21160525 J Pathol. 2008 Jan;214(1):17-24 17948228 Carcinoma, Squamous Cell genetics Case-Control Studies Cell Line, Tumor DNA Methylation Gene Expression Profiling Humans Laryngeal Neoplasms genetics MicroRNAs genetics Mouth Neoplasms genetics Oropharyngeal Neoplasms genetics Polymerase Chain Reaction Sensitivity and Specificity Tumor Markers, Biological genetics NIHMS343651 PMC3291120 2011 6 15 2011 11 3 2011 11 7 2011 11 30 2011 12 3 6 0 2011 12 3 6 0 2012 6 1 6 0 ppublish S1368-8375(11)00885-2 10.1016/j.oraloncology.2011.11.006 22133638 PMC3291120 NIHMS343651 22132151 2011 12 01 2012 04 02 2013 10 15

1932-6203 6 11 2011 PLoS ONE MicroRNA alterations and associated aberrant DNA methylation patterns across multiple sample types in oral squamous cell carcinoma. e27840 10.1371/journal.pone.0027840 MicroRNA (miRNA) expression is broadly altered in cancer, but few studies have investigated miRNA deregulation in oral squamous cell carcinoma (OSCC). Epigenetic mechanisms are involved in the regulation of >30 miRNA genes in a range of tissues, and we aimed to investigate this further in OSCC. TaqMan® qRT-PCR arrays and individual assays were used to profile miRNA expression in a panel of 25 tumors with matched adjacent tissues from patients with OSCC, and 8 control paired oral stroma and epithelium from healthy volunteers. Associated DNA methylation changes of candidate epigenetically deregulated miRNA genes were measured in the same samples using the MassArray® mass spectrometry platform. MiRNA expression and DNA methylation changes were also investigated in FACS sorted CD44(high) oral cancer stem cells from primary tumor samples (CSCs), and in oral rinse and saliva from 15 OSCC patients and 7 healthy volunteers. MiRNA expression patterns were consistent in healthy oral epithelium and stroma, but broadly altered in both tumor and adjacent tissue from OSCC patients. MiR-375 is repressed and miR-127 activated in OSCC, and we confirm previous reports of miR-137 hypermethylation in oral cancer. The miR-200 s/miR-205 were epigenetically activated in tumors vs normal tissues, but repressed in the absence of DNA hypermethylation specifically in CD44(high) oral CSCs. Aberrant miR-375 and miR-200a expression and miR-200c-141 methylation could be detected in and distinguish OSCC patient oral rinse and saliva from healthy volunteers, suggesting a potential clinical application for OSCC specific miRNA signatures in oral fluids. MiRNA expression and DNA methylation changes are a common event in OSCC, and we suggest miR-375, miR-127, miR-137, the miR-200 family and miR-205 as promising candidates for future investigations. Although overall activated in OSCC, miR-200/miR-205 suppression in oral CSCs indicate that cell specific silencing of these miRNAs may drive tumor expansion and progression. Wiklund Erik D ED Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. Gao Shan S Hulf Toby T Sibbritt Tennille T Nair Shalima S Costea Daniela Elena DE Villadsen Sune B SB Bakholdt Vivi V Bramsen Jesper B JB Sørensen Jens A JA Krogdahl Annelise A Clark Susan J SJ Kjems Jørgen J eng Journal Article Research Support, Non-U.S. Gov't 2011 11 22

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1083-351X 287 8 2012 Feb 17 J. Biol. Chem. DNA methylation-regulated miR-193a-3p dictates resistance of hepatocellular carcinoma to 5-fluorouracil via repression of SRSF2 expression. 5639-49 10.1074/jbc.M111.291229 Chemoresistance prevents effective cancer therapy and is rarely predictable prior to treatment, particularly for hepatocellular carcinoma (HCC). Following the chemoresistance profiling of eight HCC cell lines to each of nine chemotherapeutics, two cell lines (QGY-7703 as a sensitive and SMMC-7721 as a resistant cell line to 5-fluorouracil (5-FU) treatment) were systematically studied for mechanistic insights underpinning HCC 5-FU chemoresistance. Genomic profiling at both DNA methylation and microRNA (miR) levels and subsequent mechanistic studies illustrate a new mechanism for how DNA methylation-regulated miR-193a-3p dictates the 5-FU resistance of HCC cells via repression of serine/arginine-rich splicing factor 2 (SRSF2) expression. In turn, SRSF2 preferentially up-regulates the proapoptotic splicing form of caspase 2 (CASP2L) and sensitizes HCC cells to 5-FU. Forced changes of miR-193a-3p level reverse all of the phenotypic features examined, including cell proliferation, cell cycle progression, and 5-FU sensitivity, in cell culture and in nude mice. Importantly, the siRNA-mediated repression of SRSF2 phenocopies all of the miR-193a-3p mimic-triggered changes in QGY-7703. This newly identified miR-193a-3p-SRSF2 axis highlights a new set of companion diagnostics required for optimal 5-FU therapy of HCC, which involve assaying both the DNA methylation state of the miR-193a gene and the expression of miR-193a-3p and SRSF2 and the relative level of the proapoptotic versus antiapoptotic splicing forms of caspase 2 in clinical samples. Ma Kelong K Shanghai Medical College, Fudan University, Shanghai 200032, China. He Yinghua Y Zhang Hongyu H Fei Qi Q Niu Dandan D Wang Dongmei D Ding Xia X Xu Hua H Chen Xiaoping X Zhu Jingde J eng Journal Article Research Support, Non-U.S. Gov't 2011 11 23

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1932-6203 6 11 2011 PLoS ONE Integrated epigenetics of human breast cancer: synoptic investigation of targeted genes, microRNAs and proteins upon demethylation treatment. e27355 10.1371/journal.pone.0027355 The contribution of aberrant DNA methylation in silencing of tumor suppressor genes (TSGs) and microRNAs has been investigated. Since these epigenetic alterations are reversible, it became of interest to determine the effects of the 5-aza-2'-deoxycytidine (DAC) demethylation therapy in breast cancer at different molecular levels. Here we investigate a synoptic model to predict complete DAC treatment effects at the level of genes, microRNAs and proteins for several human breast cancer lines. The present study assessed an effective treatment dosage based on the cell viability, cytotoxicity, apoptosis and methylation assays for the investigated cell lines. A highly aggressive and a non-aggressive cell line were investigated using omics approaches such as MALDI-TOF MS, mRNA- and microRNA expression arrays, 2-D gel electrophoresis and LC-MS-MS. Complete molecular profiles including the biological interaction and possible early and late systematic stable or transient effects of the methylation inhibition were determined. Beside the activation of several epigenetically suppressed TSGs, we also showed significant dysregulation of some important oncogenes, oncomiRs and oncosuppressors miRNAs as well as drug tolerance genes/miRNAs/proteins. In the present study, the results denote some new molecular DAC targets and pathways based on the chemical modification of DNA methylation in breast cancer. The outlined approach might prove to be useful as an epigenetic treatment model also for other human solid tumors in the management of cancer patients. Radpour Ramin R Laboratory for Gynecological Oncology, Department of Biomedicine/Women's Hospital, University of Basel, Basel, Switzerland. Barekati Zeinab Z Kohler Corina C Schumacher Martin M MM Grussenmeyer Thomas T Jenoe Paul P Hartmann Nicole N Moes Suzette S Letzkus Martin M Bitzer Johannes J Lefkovits Ivan I Staedtler Frank F Zhong Xiao Yan XY eng Journal Article Research Support, Non-U.S. Gov't 2011 11 04

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1083-351X 287 1 2012 Jan 2 J. Biol. Chem. MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells. 465-73 10.1074/jbc.M111.280768 Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs. Yu Fengyan F Department of Breast Surgery, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China. Jiao Yu Y Zhu Yinghua Y Wang Ying Y Zhu Jingde J Cui Xiuying X Liu Yujie Y He Yinghua Y Park Eun-Young EY Zhang Hongyu H Lv Xiaobin X Ma Kelong K Su Fengxi F Park Jong Hoon JH Song Erwei E eng Journal Article Research Support, Non-U.S. Gov't 2011 11 10

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1932-6203 6 11 2011 PLoS ONE Time to recurrence and survival in serous ovarian tumors predicted from integrated genomic profiles. e24709 10.1371/journal.pone.0024709 Serous ovarian cancer (SeOvCa) is an aggressive disease with differential and often inadequate therapeutic outcome after standard treatment. The Cancer Genome Atlas (TCGA) has provided rich molecular and genetic profiles from hundreds of primary surgical samples. These profiles confirm mutations of TP53 in ~100% of patients and an extraordinarily complex profile of DNA copy number changes with considerable patient-to-patient diversity. This raises the joint challenge of exploiting all new available datasets and reducing their confounding complexity for the purpose of predicting clinical outcomes and identifying disease relevant pathway alterations. We therefore set out to use multi-data type genomic profiles (mRNA, DNA methylation, DNA copy-number alteration and microRNA) available from TCGA to identify prognostic signatures for the prediction of progression-free survival (PFS) and overall survival (OS). We implemented a multivariate Cox Lasso model and median time-to-event prediction algorithm and applied it to two datasets integrated from the four genomic data types. We (1) selected features through cross-validation; (2) generated a prognostic index for patient risk stratification; and (3) directly predicted continuous clinical outcome measures, that is, the time to recurrence and survival time. We used Kaplan-Meier p-values, hazard ratios (HR), and concordance probability estimates (CPE) to assess prediction performance, comparing separate and integrated datasets. Data integration resulted in the best PFS signature (withheld data: p-value = 0.008; HR = 2.83; CPE = 0.72). We provide a prediction tool that inputs genomic profiles of primary surgical samples and generates patient-specific predictions for the time to recurrence and survival, along with outcome risk predictions. Using integrated genomic profiles resulted in information gain for prediction of outcomes. Pathway analysis provided potential insights into functional changes affecting disease progression. The prognostic signatures, if prospectively validated, may be useful for interpreting therapeutic outcomes for clinical trials that aim to improve the therapy for SeOvCa patients. Mankoo Parminder K PK Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. Shen Ronglai R Schultz Nikolaus N Levine Douglas A DA Sander Chris C eng U24 CA143840 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2011 11 03

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1000-467X 32 1 2013 Jan Chin J Cancer Epigenetic changes in colorectal cancer. 21-30 10.5732/cjc.011.10245 Epigenetic changes frequently occur in human colorectal cancer. Genomic global hypomethylation, gene promoter region hypermethylation, histone modifications, and alteration of miRNA patterns are major epigenetic changes in colorectal cancer. Loss of imprinting(LOI) is associated with colorectal neoplasia. Folate deficiency may cause colorectal carcinogenesis by inducing gene-specific hypermethylation and genomic global hypomethylation. HDAC inhibitors and demethylating agents have been approved by the FDA for myelodysplastic syndrome and leukemia treatment. Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer. This review is mainly focused on DNA methylation, histone modification, and microRNA changes in colorectal cancer. Jia Yan Y Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, People's Republic of China. Guo Mingzhou M eng Journal Article Research Support, Non-U.S. Gov't Review 2011 11 04

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1932-8494 294 11 2011 Nov Anat Rec (Hoboken) DNA methylation and nonsmall cell lung cancer. 1787-95 10.1002/ar.21471 Lung cancer is the leading cause of cancer-related death in men and women worldwide. Owing to the scarcity of effective tools for early detection and therapy strategies, the 5-year survival rate of lung cancer is very poor. Because the accumulation of multiple genetic and/or epigenetic changes, including DNA methylation, has been suggested to contribute to development and progression of human cancers, improved understanding of the relationship between DNA methylation and lung cancer will provide new insights for identifying promising biomarkers for diagnosis, prognosis, and treatment of lung cancer. Here, we present a relatively comprehensive review of DNA methylation and lung cancer, discuss DNA methylation changes in carcinogenesis and metastasis of lung cancer, and explore the association of microRNA with DNA methylation. Additionally, we outline the applications of DNA methylation in clinical practice, such as diagnosis, prognosis, and therapy of lung cancer. Copyright © 2011 Wiley-Liss, Inc. Lu Fang F Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University, Suzhou, Jiangsu Province, People's Republic of China. Zhang Hong-Tao HT eng Journal Article Research Support, Non-U.S. Gov't Review 2011 09 28

United States Anat Rec (Hoboken) 101292775 1932-8486 0 MicroRNAs IM Animals Carcinoma, Non-Small-Cell Lung genetics secondary therapy DNA Methylation Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Humans Lung Neoplasms genetics pathology therapy MicroRNAs metabolism Neoplasm Invasiveness Phenotype Prognosis 2011 6 11 2011 7 13 2011 7 22 2011 9 28 2011 9 30 6 0 2011 10 1 6 0 2012 2 2 6 0 ppublish 10.1002/ar.21471 21956844 21949788 2011 09 28 2012 02 03 2013 10 16

1932-6203 6 9 2011 PLoS ONE Epigenetic regulation of microRNA genes and the role of miR-34b in cell invasion and motility in human melanoma. e24922 10.1371/journal.pone.0024922 Invasive melanoma is the most lethal form of skin cancer. The treatment of melanoma-derived cell lines with 5-aza-2'-deoxycytidine (5-Aza-dC) markedly increases the expression of several miRNAs, suggesting that the miRNA-encoding genes might be epigenetically regulated, either directly or indirectly, by DNA methylation. We have identified a group of epigenetically regulated miRNA genes in melanoma cells, and have confirmed that the upstream CpG island sequences of several such miRNA genes are hypermethylated in cell lines derived from different stages of melanoma, but not in melanocytes and keratinocytes. We used direct DNA bisulfite and immunoprecipitated DNA (Methyl-DIP) to identify changes in CpG island methylation in distinct melanoma patient samples classified as primary in situ, regional metastatic, and distant metastatic. Two melanoma cell lines (WM1552C and A375 derived from stage 3 and stage 4 human melanoma, respectively) were engineered to ectopically express one of the epigenetically modified miRNA: miR-34b. Expression of miR-34b reduced cell invasion and motility rates of both WM1552C and A375, suggesting that the enhanced cell invasiveness and motility observed in metastatic melanoma cells may be related to their reduced expression of miR-34b. Total RNA isolated from control or miR-34b-expressing WM1552C cells was subjected to deep sequencing to identify gene networks around miR-34b. We identified network modules that are potentially regulated by miR-34b, and which suggest a mechanism for the role of miR-34b in regulating normal cell motility and cytokinesis. Mazar Joseph J Sanford Burnham Medical Research Institute, Orlando, Florida, United States of America. Khaitan Divya D DeBlasio Dan D Zhong Cuncong C Govindarajan Subramaniam S SS Kopanathi Sharmila S Zhang Shaojie S Ray Animesh A Perera Ranjan J RJ eng 1R01GM084881-01 GM NIGMS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2011 09 19

United States PLoS One 101285081 1932-6203 0 MIRN34 microRNA, human 0 MicroRNAs 0 RNA, Messenger 0 Tumor Markers, Biological IM Am J Pathol. 2000 Mar;156(3):769-74 10702391 Nat Genet. 2002 Jun;31(2):141-9 11992124 EMBO J. 2001 Jun 1;20(11):2631-40 11387198 J Cell Biol. 1998 Jan 26;140(2):419-30 9442117 Am J Pathol. 1999 Aug;155(2):441-52 10433937 Cancer Cell. 2006 Jun;9(6):435-43 16766263 Oncogene. 2006 Aug 17;25(36):5027-36 16568085 Oncogene. 2006 Dec 4;25(57):7469-81 17143291 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Br J Cancer. 2007 Feb 26;96(4):646-53 17245340 Nat Rev Genet. 2007 Apr;8(4):286-98 17339880 BioDrugs. 2007;21(2):97-104 17402793 PLoS Comput Biol. 2007 Mar 9;3(3):e37 17352530 PLoS Genet. 2007 Sep;3(9):1709-23 17892325 Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17719-24 17965236 Cancer Biol Ther. 2007 Aug;6(8):1284-8 17660710 Cancer Res. 2008 Mar 1;68(5):1362-8 18316599 Semin Cancer Biol. 2008 Apr;18(2):111-22 18296065 Cancer Res. 2008 Apr 15;68(8):2745-54 18417445 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Nat Methods. 2008 Jul;5(7):621-8 18516045 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Cell Cycle. 2008 Aug 15;7(16):2591-600 18719384 Cancer Cell. 2002 Apr;1(3):279-88 12086864 Nature. 2002 Aug 15;418(6899):790-3 12181570 Biochim Biophys Acta. 2002 Oct 9;1588(1):1-6 12379307 Cancer Res. 1990 Nov 1;50(21):6981-6 2208165 Biochemistry. 1996 Mar 19;35(11):3518-24 8639502 Curr Biol. 1997 Jul 1;7(7):479-87 9210375 Melanoma Res. 1997 Oct;7(5):393-9 9429222 Genes Dev. 2008 Nov 15;22(22):3172-83 19056895 Genome Res. 2009 Jan;19(1):92-105 18955434 J Thorac Oncol. 2009 Apr;4(4):455-62 19240652 J Hepatol. 2009 May;50(5):948-57 19303159 Nat Genet. 2009 May;41(5):518-20 19330028 J Invest Dermatol. 2009 Jul;129(7):1740-51 19212343 Cancer Control. 2009 Jul;16(3):200-18 19556960 Int J Cancer. 2009 Oct 1;125(7):1514-22 19521982 Br J Cancer. 2009 Aug 18;101(4):551-6 19638982 J Mol Diagn. 2009 Sep;11(5):420-9 19710399 Cancer Cell. 2009 Sep 8;16(3):246-58 19732724 PLoS One. 2009;4(10):e7629 19893619 PLoS One. 2009;4(11):e7767 19907642 Oncogene. 2009 Nov 19;28(46):4065-74 19734943 Nucleic Acids Res. 2010 Jan;38(Database issue):D613-9 19906737 Clin Cancer Res. 2010 Mar 1;16(5):1577-86 20179230 PLoS One. 2010;5(3):e9685 20300190 PLoS Pathog. 2010 Mar;6(3):e1000820 20333250 Cancer Lett. 2010 May 1;291(1):99-107 19900756 Cancer Res. 2010 May 15;70(10):4163-73 20442294 J Natl Cancer Inst. 2010 Jun 2;102(11):812-27 20484106 Eur J Cancer. 2010 Jun;46(9):1692-702 20371173 J Transl Med. 2010;8:56 20540720 J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):110-3 20153427 Gan To Kagaku Ryoho. 2010 Sep;37(9):1650-3 20841926 Cancer Res. 2010 Sep 15;70(18):7027-30 20807816 J Invest Dermatol. 2010 Dec;130(12):2809-17 20703244 PLoS One. 2010;5(11):e13779 21072171 Mol Cell. 2010 Dec 10;40(5):841-9 21109473 FEBS Lett. 2011 Aug 4;585(15):2467-76 21723283 J Biol Chem. 2001 Jun 15;276(24):21209-16 11399775 Am J Pathol. 2000 Oct;157(4):1123-8 11021816 Blotting, Northern Cell Adhesion Cell Line, Tumor Cell Movement CpG Islands DNA Methylation Epigenomics Gene Expression Profiling Gene Expression Regulation, Neoplastic Gene Silencing Humans Melanoma genetics secondary MicroRNAs genetics Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic genetics RNA, Messenger genetics Real-Time Polymerase Chain Reaction Skin Neoplasms genetics metabolism pathology Tumor Markers, Biological genetics metabolism Wound Healing PMC3176288 2011 7 12 2011 8 18 2011 9 19 2011 9 28 6 0 2011 9 29 6 0 2012 2 4 6 0 ppublish 10.1371/journal.pone.0024922 PONE-D-11-13352 21949788 PMC3176288 21949547 2011 9 27

1868-7075 2 2 2011 Aug Clin Epigenetics MicroRNA-mediated drug resistance in breast cancer. 171-185 Chemoresistance is one of the major hurdles to overcome for the successful treatment of breast cancer. At present, there are several mechanisms proposed to explain drug resistance to chemotherapeutic agents, including decreased intracellular drug concentrations, mediated by drug transporters and metabolic enzymes; impaired cellular responses that affect cell cycle arrest, apoptosis, and DNA repair; the induction of signaling pathways that promote the progression of cancer cell populations; perturbations in DNA methylation and histone modifications; and alterations in the availability of drug targets. Both genetic and epigenetic theories have been put forward to explain the mechanisms of drug resistance. Recently, a small non-coding class of RNAs, known as microRNAs, has been identified as master regulators of key genes implicated in mechanisms of chemoresistance. This article reviews the role of microRNAs in regulating chemoresistance and highlights potential therapeutic targets for reversing miRNA-mediated drug resistance. In the future, microRNA-based treatments, in combination with traditional chemotherapy, may be a new strategy for the clinical management of drug-resistant breast cancers. Kutanzi Kristy R KR Yurchenko Olga V OV Beland Frederick A FA Checkhun Vasyl' F VF Pogribny Igor P IP ENG JOURNAL ARTICLE 2011 6 27

Clin Epigenetics 101516977 1868-7075 2011 4 26 2011 5 18 2011 6 27 2011 9 28 6 0 2011 9 29 6 0 2011 9 29 6 0 ppublish 10.1007/s13148-011-0040-8 40 21949547 PMC3156306 21917081 2011 11 21 2012 01 20

1349-7006 102 12 2011 Dec Cancer Sci. CpG island methylation of microRNAs is associated with tumor size and recurrence of non-small-cell lung cancer. 2126-31 10.1111/j.1349-7006.2011.02101.x We investigated whether the CpG island methylation of certain microRNAs was associated with the clinicopathological features and the prognosis of non-small-cell lung cancer. The methylation of mir-152, -9-3, -124-1, -124-2, and -124-3 was analyzed in 96 non-small-cell lung cancer specimens using a combined bisulfite restriction analysis. The median observation period was 49.5 months. The methylation of mir-9-3, -124-2, and -124-3 was individually associated with an advanced T factor independent of age, sex, and smoking habit. Moreover, the methylation of multiple microRNA loci was associated with a poorer progression-free survival in a univariate analysis. Our result enlightens the accumulation of aberrant DNA methylation which occurs in concordance with the tumor progression. © 2011 Japanese Cancer Association. Kitano Kentaro K Department of Thoracic Surgery, The University of Tokyo Hospital, Tokyo, Japan. Watanabe Kousuke K Emoto Noriko N Kage Hidenori H Hamano Emi E Nagase Takahide T Sano Atsushi A Murakawa Tomohiro T Nakajima Jun J Goto Akiteru A Fukayama Masashi M Yatomi Yutaka Y Ohishi Nobuya N Takai Daiya D eng Journal Article Research Support, Non-U.S. Gov't 2011 10 12

England Cancer Sci 101168776 1347-9032 0 MicroRNAs IM Aged Carcinoma, Non-Small-Cell Lung genetics metabolism pathology CpG Islands DNA Methylation Disease Progression Female Humans Kaplan-Meier Estimate Lung Neoplasms genetics metabolism pathology Male MicroRNAs genetics metabolism Middle Aged Neoplasm Recurrence, Local 2011 10 12 2011 9 16 6 0 2011 9 16 6 0 2012 1 21 6 0 ppublish 10.1111/j.1349-7006.2011.02101.x 21917081 21914401 2011 09 14 2012 04 30

0376-2491 91 23 2011 Jun 21 Zhonghua Yi Xue Za Zhi [DNA methylation of microRNA-34b/c and microRNA-124a in gastric cancer]. 1640-2 To explore the effects of DNA methylation of microRNA (miRNA) gene on their expressions in patients with gastric carcinoma. A total of 80 subjects were divided into gastric carcinoma group (n = 40) and control group (n = 40). The DNA methylation status of miRNA-34b/c and miRNA-124a gene promoters was detected by DNA methylation specific polymerase chain reaction (MSP) in gastric carcinoma tissues and normal mucosal tissues. The positive rate of DNA methylation of miRNA-34b/c gene promoter was 77.5% (31/40) and 5.0% (2/40) in gastric carcinoma and control groups respectively. There was statistically significant difference between two groups (P < 0.05). The positive rate of DNA methylation of miRNA-124a gene promoter was 60.0% (24/40) and 0 in these two groups respectively. There was statistically significant difference between two groups (P < 0.05). Also the hypermethylation positivity of gene promoter of miRNAs was correlated with the clinicopathological features of gastric carcinoma. The hypermethylation of miRNA-34b/c and miRNA-124a gene promoters may play a crucial role in the occurrence and development of gastric carcinoma. Li Yang Y Department of Gastroenterology, Tianjin Medical University Hospital, Tianjin 300052, China. Yue Hong-yu HY Liu Wen-tian WT Fang Wei-li WL chi English Abstract Journal Article

China Zhonghua Yi Xue Za Zhi 7511141 0376-2491 0 MIRN124 microRNA, human 0 MIRN34 microRNA, human 0 MicroRNAs IM DNA Methylation Female Humans Male MicroRNAs genetics Middle Aged Promoter Regions, Genetic Stomach Neoplasms pathology 2011 9 15 6 0 2011 9 15 6 0 2012 5 1 6 0 ppublish 21914401 21874049 2012 04 19 2012 06 20 2013 10 16

1476-5594 31 16 2012 Apr 19 Oncogene Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. 2062-74 10.1038/onc.2011.383 Epithelial-mesenchymal (EMT) and mesenchymal-epithelial (MET) transitions occur in the development of human tumorigenesis and are part of the natural history of the process to adapt to the changing microenvironment. In this setting, the miR-200 family is recognized as a master regulator of the epithelial phenotype by targeting ZEB1 and ZEB2, two important transcriptional repressors of the cell adherence (E-cadherin) and polarity (CRB3 and LGL2) genes. Recently, the putative DNA methylation associated inactivation of various miR-200 members has been described in cancer. Herein, we show that the miR-200ba429 and miR-200c141 transcripts undergo a dynamic epigenetic regulation linked to EMT or MET phenotypes in tumor progression. The 5'-CpG islands of both miR-200 loci were found unmethylated and coupled to the expression of the corresponding miRNAs in human cancer cell lines with epithelial features, such as low levels of ZEB1/ZEB2 and high expression of E-cadherin, CRB3 and LGL2, while CpG island hypermethylation-associated silencing was observed in transformed cells with mesenchymal characteristics. The recovery of miR-200ba429 and miR-200c141 expression by stable transfection in the hypermethylated cells restored the epithelial markers and inhibited migration in cell culture and tumoral growth and metastasis formation in nude mice. We also discovered, using both cell culture and animal models, that the miR-200 epigenetic silencing is not an static and fixed process but it can be shifted to hypermethylated or unmethylated 5'-CpG island status corresponding to the EMT and MET phenotypes, respectively. In fact, careful laser microdissection in human primary colorectal tumorigenesis unveiled that in normal colon mucosa crypts (epithelia) and stroma (mesenchyma) already are unmethylated and methylated at these loci, respectively; and that the colorectal tumors undergo selective miR-200 hypermethylation of their epithelial component. These findings indicate that the epigenetic silencing plasticity of the miR-200 family contributes to the evolving and adapting phenotypes of human tumors. Davalos V V Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain. Moutinho C C Villanueva A A Boque R R Silva P P Carneiro F F Esteller M M eng Journal Article Research Support, Non-U.S. Gov't 2011 08 29

England Oncogene 8711562 0950-9232 0 Homeodomain Proteins 0 MIRN200 microRNA, human 0 MicroRNAs 0 Repressor Proteins 0 Transcription Factors 0 ZEB1 protein, human 0 ZEB2 protein, human IM Clin Cancer Res. 2007 Mar 15;13(6):1634-7 17363514 Cell. 2007 Feb 23;128(4):683-92 17320506 Cells Tissues Organs. 2007;185(1-3):7-19 17587803 RNA. 2007 Aug;13(8):1172-8 17585049 J Cell Physiol. 2007 Nov;213(2):374-83 17680632 Cancer Res. 2007 Sep 1;67(17):7972-6 17804704 Oncogene. 2007 Oct 25;26(49):6979-88 17486063 Cancer Res. 2008 Jan 15;68(2):537-44 18199550 N Engl J Med. 2008 Mar 13;358(11):1148-59 18337604 Genes Dev. 2008 Apr 1;22(7):894-907 18381893 Nat Cell Biol. 2008 May;10(5):593-601 18376396 J Biol Chem. 2008 May 30;283(22):14910-4 18411277 EMBO Rep. 2008 Jun;9(6):582-9 18483486 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Dev Cell. 2008 Jun;14(6):818-29 18539112 J Biol Chem. 2008 Jul 25;283(30):21065-73 18499657 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Cell Cycle. 2008 Aug 15;7(16):2485-92 18719380 Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14867-72 18806226 Cancer Res. 2008 Oct 1;68(19):7846-54 18829540 Nat Rev Mol Cell Biol. 2008 Nov;9(11):887-901 18946477 Oncogene. 2008 Nov 24;27(55):6958-69 19029937 Oncogene. 2008 Nov 24;27(55):6970-80 19029938 Cell Res. 2009 Feb;19(2):156-72 19153598 Nat Rev Cancer. 2009 Apr;9(4):265-73 19262571 J Clin Invest. 2009 Jun;119(6):1420-8 19487818 J Clin Invest. 2009 Jun;119(6):1429-37 19487819 J Clin Invest. 2009 Jun;119(6):1438-49 19487820 J Pathol. 2009 Oct;219(2):214-21 19593777 Genes Dev. 2009 Sep 15;23(18):2140-51 19759262 Proc Natl Acad Sci U S A. 2001 Aug 28;98(18):10356-61 11526241 Nat Rev Cancer. 2002 Jun;2(6):442-54 12189386 Gastroenterology. 2002 Dec;123(6):1941-8 12454851 Oncogene. 2005 Aug 29;24(37):5764-74 16123809 Clin Exp Metastasis. 2005;22(4):351-61 16170671 Nucleic Acids Res. 2005;33(20):e179 16314309 PLoS One. 2009;4(9):e7181 19787069 Nat Protoc. 2009;4(11):1591-613 19834475 Cell. 2009 Nov 25;139(5):871-90 19945376 Cancer Res. 2009 Dec 1;69(23):9038-46 19887623 PLoS One. 2010;5(1):e8697 20084174 Cancer. 2010 Feb 1;116(3):544-73 19998273 Curr Opin Genet Dev. 2010 Feb;20(1):41-50 20093003 Eur J Clin Invest. 2010 Apr;40(4):370-4 20486997 Oncogene. 2010 Sep 2;29(35):4896-904 20562920 Mol Cancer Res. 2010 Sep;8(9):1207-16 20696752 Expert Opin Ther Targets. 2010 Nov;14(11):1213-23 20925461 Science. 2010 Oct 29;330(6004):576-8 21030620 J Pathol. 2011 Jan;223(1):72-80 21125666 Int J Cancer. 2011 Mar 15;128(6):1327-34 20473948 Int J Cancer. 2011 Apr 1;128(7):1585-95 20533280 Cell Stem Cell. 2011 May 6;8(5):525-37 21549327 Oncogene. 2011 May 12;30(19):2230-41 21258411 J Biol Chem. 2011 Jul 22;286(29):25992-6002 21596753 J Cell Sci. 2009 Jul 15;122(Pt 14):2473-80 19549682 Cancer Cell. 2006 Jun;9(6):435-43 16766263 Cell Cycle. 2006 Sep;5(17):1951-6 16929162 J Natl Cancer Inst. 2006 Oct 18;98(20):1443-4 17047192 Cancer Res. 2006 Dec 1;66(23):11271-8 17145872 Biochim Biophys Acta. 2007 Jan;1775(1):21-62 16904831 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Nat Rev Cancer. 2007 Jun;7(6):415-28 17508028 Animals Cell Line, Tumor Cell Movement genetics Cell Proliferation Cell Transformation, Neoplastic genetics Colonic Neoplasms genetics CpG Islands DNA Methylation Epithelial-Mesenchymal Transition Gene Silencing Homeodomain Proteins genetics Humans Mice Mice, Nude MicroRNAs metabolism Neoplasm Metastasis genetics Neoplasm Transplantation Neoplasms genetics pathology Repressor Proteins genetics Transcription Factors genetics Up-Regulation PMC3330264 2011 8 29 2011 8 30 6 0 2011 8 30 6 0 2012 6 21 6 0 ppublish onc2011383 10.1038/onc.2011.383 21874049 PMC3330264 21868754 2011 10 14 2011 12 12 2012 06 04

1538-7445 71 20 2011 Oct 15 Cancer Res. miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. 6450-62 10.1158/0008-5472.CAN-11-0364 The etiology and development of human cancers that remain little understood might be enlightened by defining tumor suppressor microRNAs (TS-miRNA). In this study, we identified TS-miRNAs silenced by aberrant DNA hypermethylation in endometrial cancer. Functional screening of 327 synthetic miRNAs in an endometrial cancer cell proliferation assay identified 103 miRNAs that inhibited cell growth. We then determined the sequence, DNA methylation status, and expression levels of these miRNAs in endometrial cancer cell lines and primary tumors. These determinations led to the identification of miR-152 as a candidate TS-miRNA gene in endometrial cancer. Epigenetic silencing documented in miR-152 was consistent with its location at 17q21.32 in intron 1 of the COPZ2 gene, which is also silenced often in endometrial cancer by DNA hypermethylation, and also with evidence that miR-152 targets the DNA methyltransferase DNMT1. Notably, restoration of miR-152 expression in endometrial cancer cell lines was sufficient to inhibit tumor cell growth in vitro and in vivo. We identified E2F3, MET, and Rictor as novel candidate targets of miR-152, suggesting how its epigenetic silencing can drive endometrial carcinogenesis. Our findings define a central role for miR-152 in endometrial cancer, and they also suggest its use in new therapeutic strategies to treat this cancer. Tsuruta Tomohiko T Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo, Japan. Kozaki Ken-Ichi K Uesugi Atsushi A Furuta Mayuko M Hirasawa Akira A Imoto Issei I Susumu Nobuyuki N Aoki Daisuke D Inazawa Johji J eng Journal Article Research Support, Non-U.S. Gov't 2011 08 25

United States Cancer Res 2984705R 0008-5472 0 Carrier Proteins 0 Coatomer Protein 0 E2F3 Transcription Factor 0 E2F3 protein, human 0 MIRN152 microRNA, human 0 MicroRNAs 0 RICTOR protein, human EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 EC 2.7.10.1 MET protein, human EC 2.7.10.1 Proto-Oncogene Proteins c-met IM Adenocarcinoma genetics metabolism Carrier Proteins metabolism Cell Line, Tumor Cell Proliferation drug effects Chromosomes, Human, Pair 17 genetics Coatomer Protein genetics DNA (Cytosine-5-)-Methyltransferase metabolism DNA Methylation E2F3 Transcription Factor metabolism Endometrial Neoplasms genetics metabolism Female Gene Silencing Genes, Tumor Suppressor Humans Introns MicroRNAs genetics metabolism Proto-Oncogene Proteins c-met metabolism 2011 8 25 2011 8 27 6 0 2011 8 27 6 0 2011 12 14 6 0 ppublish 0008-5472.CAN-11-0364 10.1158/0008-5472.CAN-11-0364 21868754 21826097 2011 11 10 2012 07 13 2013 04 03

1476-5608 14 4 2011 Dec Prostate Cancer Prostatic Dis. Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer. 279-85 10.1038/pcan.2011.33 Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post-transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3'UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches. Darimipourain M M Howard University Cancer Center, Washington, DC 20060, USA. Wang S S Ittmann M M Kwabi-Addo B B eng P20 CA103698 CA NCI NIH HHS United States P50CA058204 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2011 08 09

England Prostate Cancer Prostatic Dis 9815755 1365-7852 0 DNA-Binding Proteins 0 MIRN21 microRNA, human 0 Membrane Proteins 0 MicroRNAs 0 Phosphoproteins 0 RNA, Messenger 0 SPRY1 protein, human 0 Transcription Factors IM Base Sequence Binding Sites Cell Line, Tumor DNA-Binding Proteins metabolism Gene Expression Regulation, Neoplastic Gene Silencing Humans Male Membrane Proteins genetics metabolism MicroRNAs metabolism Molecular Sequence Data Phosphoproteins genetics metabolism Promoter Regions, Genetic Prostatic Neoplasms genetics metabolism RNA, Messenger metabolism Sequence Alignment Transcription Factors metabolism Transcription, Genetic 2011 8 09 2011 8 10 6 0 2011 8 10 6 0 2012 7 14 6 0 ppublish pcan201133 10.1038/pcan.2011.33 21826097 21795477 2011 09 01 2011 10 25

1538-7445 71 17 2011 Sep 1 Cancer Res. The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer. 5765-78 10.1158/0008-5472.CAN-11-0368 The incidence of oral squamous cell carcinoma (OSCC) is rising rapidly in developed countries, posing a growing challenge due to the poor management of this type of malignancy at present. In this study, we profiled tumor suppressive microRNAs (miRNAs) that are silenced by DNA hypermethylation in OSCC using a function-based screening approach. This approach employed a cell proliferation assay for 327 synthetic miRNAs in two OSCC cell lines. Among the 110 miRNAs identified in this set that exhibited inhibitory properties, we compared DNA methylation and expression status in a wider panel of OSCC cell lines and primary tumor tissues, resulting in the identification of miR-218 and miR-585 as functionally significant miRNA genes that are frequently silenced in OSCC by DNA hypermethylation. Ectopic expression of miR-218 and miR-585 in OSCC cells lacking endogenous expression reduced cell growth in part through caspase-mediated apoptosis. Notably, miR-218 reduced levels of the rapamycin-insensitive component of mTOR, Rictor, in a manner associated with a suppression of Akt S473 phosphorylation. Together our findings define miR-585 as a tumor suppressive function that is often epigenetically silenced in OSCC, and they identify Rictor as a novel target of miR-218, suggesting that activation of the mTOR-Akt signaling pathway induced by Rictor contributes centrally to oral carcinogenesis. ©2011 AACR. Uesugi Atsushi A Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo, Japan. Kozaki Ken-Ichi K Tsuruta Tomohiko T Furuta Mayuko M Morita Kei-Ichi K Imoto Issei I Omura Ken K Inazawa Johji J eng Journal Article Research Support, Non-U.S. Gov't 2011 07 27

United States Cancer Res 2984705R 0008-5472 0 Carrier Proteins 0 MIRN218 microRNA, human 0 MicroRNAs 0 RICTOR protein, human EC 2.7.1.1 MTOR protein, human EC 2.7.1.1 TOR Serine-Threonine Kinases EC 2.7.11.1 Proto-Oncogene Proteins c-akt IM Carcinoma, Squamous Cell genetics pathology Carrier Proteins genetics Cell Line, Tumor Cell Transformation, Neoplastic genetics Genes, Tumor Suppressor Humans MicroRNAs genetics Mouth Neoplasms genetics Phosphorylation Proto-Oncogene Proteins c-akt metabolism TOR Serine-Threonine Kinases metabolism 2011 7 27 2011 7 29 6 0 2011 7 29 6 0 2011 10 26 6 0 ppublish 0008-5472.CAN-11-0368 10.1158/0008-5472.CAN-11-0368 21795477 21727940 2011 08 08 2011 12 01

1759-4766 7 8 2011 Aug Nat Rev Neurol Integration and analysis of genome-scale data from gliomas. 439-50 10.1038/nrneurol.2011.100 Primary brain tumors are a leading cause of cancer-related mortality among young adults and children. The most common primary malignant brain tumor, glioma, carries a median survival of only 14 months. Two major multi-institutional programs, the Glioma Molecular Diagnostic Initiative and The Cancer Genome Atlas, have pursued a comprehensive genomic characterization of a large number of clinical glioma samples using a variety of technologies to measure gene expression, chromosomal copy number alterations, somatic and germline mutations, DNA methylation, microRNA, and proteomic changes. Classification of gliomas on the basis of gene expression has revealed six major subtypes and provided insights into the underlying biology of each subtype. Integration of genome-wide data from different technologies has been used to identify many potential protein targets in this disease, while increasing the reliability and biological interpretability of results. Mapping genomic changes onto both known and inferred cellular networks represents the next level of analysis, and has yielded proteins with key roles in tumorigenesis. Ultimately, the information gained from these approaches will be used to create customized therapeutic regimens for each patient based on the unique genomic signature of the individual tumor. In this Review, we describe efforts to characterize gliomas using genomic data, and consider how insights gained from these analyses promise to increase understanding of the biological underpinnings of the disease and lead the way to new therapeutic strategies. Riddick Gregory G The Neuro-Oncology Branch, National Cancer Institute, National Institute of Neurological Disease and Stroke, National Institutes of Health, The Bloch Building, 9030 Old Georgetown Road, Bethesda, MD 20892, USA. Fine Howard A HA eng Journal Article Review 2011 07 05

England Nat Rev Neurol 101500072 1759-4758 0 MicroRNAs IM Brain Neoplasms classification genetics pathology Computational Biology Data Interpretation, Statistical Epigenomics Gene Dosage Gene Expression Profiling Genomics Glioma classification genetics pathology Humans Individualized Medicine MicroRNAs genetics Proteomics 2011 7 05 2011 7 6 6 0 2011 7 6 6 0 2011 12 13 0 0 epublish nrneurol.2011.100 10.1038/nrneurol.2011.100 21727940 21719191 2011 08 31 2012 01 10

1873-7560 60 4 2011 Oct Eur. Urol. Epigenetics in prostate cancer: biologic and clinical relevance. 753-66 10.1016/j.eururo.2011.06.035 Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic. Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. Jerónimo Carmen C Cancer Epigenetics Group-Research Center, Department of Genetics, Portuguese Oncology Institute-Porto, Portugal. carmenjeronimo@ipoporto.min-saude.pt Bastian Patrick J PJ Bjartell Anders A Carbone Giuseppina M GM Catto James W F JW Clark Susan J SJ Henrique Rui R Nelson William G WG Shariat Shahrokh F SF eng Journal Article Research Support, Non-U.S. Gov't Review 2011 06 22

Switzerland Eur Urol 7512719 0302-2838 0 AR protein, human 0 Antineoplastic Agents 0 Histone Deacetylase Inhibitors 0 Histones 0 MicroRNAs 0 Receptors, Androgen EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase IM Antineoplastic Agents therapeutic use Apoptosis genetics Carcinoma diagnosis drug therapy genetics metabolism Cell Transformation, Neoplastic genetics metabolism Chromatin Assembly and Disassembly genetics DNA (Cytosine-5-)-Methyltransferase antagonists & inhibitors DNA Methylation Epigenomics Gene Expression Regulation, Neoplastic Genomic Instability Histone Deacetylase Inhibitors therapeutic use Histones metabolism Humans Male MicroRNAs metabolism Prostatic Neoplasms diagnosis drug therapy genetics metabolism Receptors, Androgen genetics metabolism 2011 5 18 2011 6 13 2011 6 22 2011 7 2 6 0 2011 7 2 6 0 2012 1 11 6 0 ppublish S0302-2838(11)00659-2 10.1016/j.eururo.2011.06.035 21719191 21705481 2011 09 28 2011 11 29

1460-2180 32 10 2011 Oct Carcinogenesis Epigenetic regulation of cellular adhesion in cancer. 1414-8 10.1093/carcin/bgr120 Epigenetics describes the development and maintenance of stable heritable gene expression patterns, which allow cells to show different phenotypes despite of a commonly shared genetic code. The increasing knowledge in this field during the last decades reveals its importance for many physiological processes like differentiation, embryogenesis and parental imprinting, but also for some diseases such as cancer. Recent data have shown that the complexity of carcinogenesis can no longer be explained solely on the basis of genetic changes, but epigenomic alterations such as changes of the DNA methylation pattern and/or post-translational histone modifications and changes of microRNA expression need to be equally considered. Such epigenetic alterations may cause permanent changes in gene expression patterns and may therefore essentially contribute to some of the known phenotypic characteristics of cancer cells like the loss of growth control, altered intercellular communication and enhanced motility. The two latter may essentially be associated with the downregulation of cellular adhesion molecules, which may therefore be relevant in the context of cancer invasiveness and prognosis. The targeted modification of the epigenome may therefore open new horizons within the increasingly important field of epigenetic therapeutics-particularly in view of the regulation of cellular adhesion with particular attention to tumor cell invasion and metastasis. Katto Judith J Department of Internal Medicine, Saarland University Medical Center, Kirrbergerstrasse, Germany. Mahlknecht Ulrich U eng Journal Article Research Support, Non-U.S. Gov't Review 2011 06 24

England Carcinogenesis 8008055 0143-3334 IM Animals Cell Adhesion physiology Epigenesis, Genetic Humans Neoplasms genetics pathology 2011 6 24 2011 7 21 2011 6 28 6 0 2011 6 28 6 0 2011 12 13 0 0 ppublish bgr120 10.1093/carcin/bgr120 21705481 21703189 2011 11 21 2012 04 05 2014 09 15

1600-0641 55 6 2011 Dec J. Hepatol. Regulation of placenta growth factor by microRNA-125b in hepatocellular cancer. 1339-45 10.1016/j.jhep.2011.04.015 microRNAs (miRNAs) are a class of small noncoding RNAs that can regulate gene expression by translation repression or mRNA degradation. Our aim was to evaluate the role of aberrantly expressed miRNAs in hepatocellular cancer (HCC). miRNA expression in HCC tissues and cells was evaluated by qPCR array and Taqman miRNA assay. Cell proliferation, motility, invasion, and the angiogenesis index were quantitated using commercial assays. DNA methylation status, matrix metalloproteinases (MMPs) mRNA expression was quantitated by real-time PCR analysis. miRNA profiling identified a decrease in miR-125b expression in HCC tumor tissues and cell lines. The expression of miR-125b was significantly increased by the methylation inhibitor 5-aza-2'-deoxycytidine in HCC cells but not in normal controls, suggesting that the expression of miR-125b could be epigenetically modulated. Methylation-specific PCR revealed hypermethylation status of miR-125b in HCC cells compared to non-malignant controls. Cell proliferation, anchorage-independent growth, cell migration, invasion, and angiogenesis were significantly decreased by the introduction of miR-125b precursor in HCC cell lines. Placenta growth factor was identified as a target of miR-125b by bioinformatics analysis and experimentally verified using luciferase reporter constructs. Overexpression of miR-125b in HCC cells decreased PIGF expression, and altered the angiogenesis index. Furthermore, modulation of miR-125b also distorted expression of MMP-2 and -9, the mediators of enzymatic degradation of the extracellular matrix. Our studies showing epigenetic silencing of miR-125b contributes to an invasive phenotype provide novel mechanistic insights and identify a potential target mechanism that could be manipulated for therapeutic benefit in HCC. Published by Elsevier B.V. Alpini Gianfranco G Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M HSC COM and Scott & White Hospital, Temple, TX 76504, USA. galpini@medicine.tamhsc.edu Glaser Shannon S SS Zhang Jing-Ping JP Francis Heather H Han Yuyan Y Gong Jiao J Stokes Allison A Francis Taylor T Hughart Nathan N Hubble Levi L Zhuang Shi-Mei SM Meng Fanyin F eng DK76898 DK NIDDK NIH HHS United States R01 DK054811 DK NIDDK NIH HHS United States R01 DK054811-05 DK NIDDK NIH HHS United States R01 DK076898 DK NIDDK NIH HHS United States R01 DK076898-03 DK NIDDK NIH HHS United States R01 DK081442 DK NIDDK NIH HHS United States R01 DK081442-02 DK NIDDK NIH HHS United States R01-DK054811 DK NIDDK NIH HHS United States R01-DK081442 DK NIDDK NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. 2011 05 19

England J Hepatol 8503886 0168-8278 0 MIRN125 microRNA, human 0 MicroRNAs 0 Pregnancy Proteins 0 RNA, Messenger 144589-93-5 placenta growth factor EC 3.4.24.24 MMP2 protein, human EC 3.4.24.24 Matrix Metalloproteinase 2 EC 3.4.24.35 Matrix Metalloproteinase 9 IM Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 Stem Cells. 2007 Jan;25(1):252-61 17008429 Hum Reprod Update. 2007 Mar-Apr;13(2):121-41 17068222 Cancer Lett. 2007 Jun 8;250(2):237-49 17137709 Gastroenterology. 2007 Aug;133(2):647-58 17681183 Liver Int. 2007 Sep;27(7):960-8 17696935 Mol Cancer Res. 2007 Sep;5(9):873-80 17704140 Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19983-8 18056640 J Hepatol. 2008 Apr;48(4):648-56 18291553 N Engl J Med. 2008 Mar 13;358(11):1148-59 18337604 Int J Cancer. 2008 Oct 1;123(7):1616-22 18649363 Cancer Res. 2009 Feb 1;69(3):1135-42 19155302 Genes Dev. 2009 Apr 1;23(7):862-76 19293287 Hepatology. 2009 Apr;49(4):1098-112 19173277 Cell Physiol Biochem. 2009;23(4-6):347-58 19471102 Int J Cancer. 2009 Jul 15;125(2):345-52 19378336 Genes Chromosomes Cancer. 2009 Jul;48(7):569-82 19396866 Cancer Res. 2009 Sep 15;69(18):7459-65 19738052 Mol Cancer Res. 2009 Oct;7(10):1635-44 19825990 Curr Opin Oncol. 2010 Jan;22(1):35-45 19907325 Clin Cancer Res. 2010 Feb 15;16(4):1129-39 20145181 Oncol Rep. 2010 Jun;23(6):1647-54 20428821 J Biol Chem. 2010 Jul 9;285(28):21496-507 20460378 Hepatology. 2010 Nov;52(5):1731-40 20827722 Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20471-6 21059911 Int J Cancer. 2011 Apr 15;128(8):1758-69 20549700 Science. 2002 Sep 13;297(5588):1807-8; discussion 1807-8 12229925 Cancer Res. 1987 Jun 15;47(12):3239-45 2438036 Proc Natl Acad Sci U S A. 1988 Aug;85(15):5693-7 2840671 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Base Sequence Carcinoma, Hepatocellular blood supply genetics metabolism pathology Case-Control Studies Cell Line, Tumor Cell Movement Endothelial Cells metabolism Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Liver Neoplasms blood supply genetics metabolism pathology Matrix Metalloproteinase 2 genetics Matrix Metalloproteinase 9 genetics MicroRNAs genetics Neoplasm Invasiveness Neovascularization, Pathologic Pregnancy Proteins metabolism RNA, Messenger genetics metabolism NIHMS298458 PMC3184370 2010 7 23 2011 3 27 2011 4 4 2011 5 19 2011 6 28 6 0 2011 6 28 6 0 2012 4 6 6 0 ppublish S0168-8278(11)00378-3 10.1016/j.jhep.2011.04.015 21703189 PMC3184370 NIHMS298458 21702040 2012 03 28 2012 05 11

1097-0215 130 11 2012 Jun 1 Int. J. Cancer Genome structure-based screening identified epigenetically silenced microRNA associated with invasiveness in non-small-cell lung cancer. 2580-90 10.1002/ijc.26254 MicroRNA (miRNA) expression is frequently altered in human cancers. To search for epigenetically silenced miRNAs in non-small-cell lung cancer (NSCLC), we mapped human miRNAs on autosomal chromosomes and selected 55 miRNAs in silico. We treated six NSCLC cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) and determined the expressions of the 55 miRNAs. Fourteen miRNAs were decreased in the cancer cell lines and were induced after 5-aza-CdR treatment. After a detailed DNA methylation analysis, we found that mir-34b and mir-126 were silenced by DNA methylation. Mir-34b was silenced by the DNA methylation of its own promoter, whereas mir-126 was silenced by the DNA methylation of its host gene, EGFL7. A chromatin immunoprecipitation assay revealed H3K9me2 and H3K9me3 in mir-34b and EGFL7, and H3K27me3 in EGFL7. The overexpression of mir-34b and mir-126 decreased the expression of c-Met and Crk, respectively. The 5-aza-CdR treatment of lung cancer cell line resulted in increased mir-34b expression and decreased c-Met protein. We next analyzed the DNA methylation status of these miRNAs using 99 primary NSCLCs. Mir-34b and mir-126 were methylated in 41 and 7% of all the cases, respectively. The DNA methylation of mir-34b was not associated with c-Met expression determined by immunohistochemistry, but both mir-34b methylation (p = 0.007) and c-Met expression (p = 0.005) were significantly associated with lymphatic invasion in a multivariate analysis. The DNA methylation of mir-34b can be used as a biomarker for an invasive phenotype of lung cancer. Copyright © 2011 UICC. Watanabe Kousuke K Department of Respiratory Medicine, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, Japan. Emoto Noriko N Hamano Emi E Sunohara Mitsuhiro M Kawakami Masanori M Kage Hidenori H Kitano Kentaro K Nakajima Jun J Goto Akiteru A Fukayama Masashi M Nagase Takahide T Yatomi Yutaka Y Ohishi Nobuya N Takai Daiya D eng Journal Article Research Support, Non-U.S. Gov't 2011 09 17

United States Int J Cancer 0042124 0020-7136 0 EGFL7 protein, human 0 Endothelial Growth Factors 0 MicroRNAs IM Adult Aged Carcinoma, Non-Small-Cell Lung genetics pathology Chromatin Immunoprecipitation DNA Methylation Endothelial Growth Factors genetics Epigenesis, Genetic Female Gene Silencing Humans Lung Neoplasms genetics pathology Male MicroRNAs physiology Middle Aged Neoplasm Invasiveness 2011 2 7 2011 6 1 2011 9 17 2011 6 25 6 0 2011 6 28 6 0 2012 5 12 6 0 ppublish 10.1002/ijc.26254 21702040 21698188 2011 06 23 2011 11 07 2013 10 16

1932-6203 6 6 2011 PLoS ONE Identification and functional analysis of epigenetically silenced microRNAs in colorectal cancer cells. e20628 10.1371/journal.pone.0020628 Abnormal microRNA (miRNA) expression has been linked to the development and progression of several human cancers, and such dysregulation can result from aberrant DNA methylation. While a small number of miRNAs is known to be regulated by DNA methylation, we postulated that such epigenetic regulation is more prevalent. By combining MBD-isolated Genome Sequencing (MiGS) to evaluate genome-wide DNA methylation patterns and microarray analysis to determine miRNA expression levels, we systematically searched for candidate miRNAs regulated by DNA methylation in colorectal cancer cell lines. We found 64 miRNAs to be robustly methylated in HCT116 cells; eighteen of them were located in imprinting regions or already reported to be regulated by DNA methylation. For the remaining 46 miRNAs, expression levels of 18 were consistent with their DNA methylation status. Finally, 8 miRNAs were up-regulated by 5-aza-2'-deoxycytidine treatment and identified to be novel miRNAs regulated by DNA methylation. Moreover, we demonstrated the functional relevance of these epigenetically silenced miRNAs by ectopically expressing select candidates, which resulted in inhibition of growth and migration of cancer cells. In addition to reporting these findings, our study also provides a reliable, systematic strategy to identify DNA methylation-regulated miRNAs by combining DNA methylation profiles and expression data. Yan Hongli H Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America. Choi Ae-Jin AJ Lee Byron H BH Ting Angela H AH eng Journal Article 2011 06 16

United States PLoS One 101285081 1932-6203 0 MicroRNAs IM Nature. 2007 Jul 5;448(7149):83-6 17589500 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Gynecol Endocrinol. 2007 Oct;23(10):567-73 17952761 Cancer Biol Ther. 2007 Aug;6(8):1284-8 17660710 J Pathol. 2008 Jan;214(1):17-24 17948228 Cancer Res. 2008 Feb 15;68(4):1092-9 18281484 Cancer Res. 2008 Apr 1;68(7):2094-105 18381414 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Cell Cycle. 2008 Aug 15;7(16):2591-600 18719384 Clin Cancer Res. 2009 Feb 15;15(4):1140-4 19228719 Int J Cancer. 2009 May 15;124(10):2367-74 19165869 Br J Haematol. 2009 May;145(3):412-23 19298589 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 Nucleic Acids Res. 2010 Jan;38(2):391-9 19906696 Carcinogenesis. 2010 Apr;31(4):745-50 20118199 Carcinogenesis. 2010 May;31(5):766-76 19843643 Methods. 2001 Dec;25(4):402-8 11846609 Nature. 2002 Apr 4;416(6880):552-6 11932749 J Biol Chem. 2003 Jan 24;278(4):2541-8 12411428 Nature. 2003 Sep 25;425(6956):415-9 14508493 Cell. 2004 Jan 23;116(2):281-97 14744438 Nat Rev Genet. 2004 Jul;5(7):522-31 15211354 Breast Cancer Res Treat. 2004 Jul;86(2):139-52 15319566 EMBO J. 2004 Oct 13;23(20):4051-60 15372072 Cytogenet Cell Genet. 1975;14(1):9-25 1093816 Nature. 1998 Jul 30;394(6692):491-4 9697773 RNA. 2004 Dec;10(12):1957-66 15525708 Nature. 2005 Jun 9;435(7043):834-8 15944708 Nucleic Acids Res. 2005;33(17):5394-403 16192569 Nucleic Acids Res. 2005;33(20):e179 16314309 Science. 2010 Jun 18;328(5985):1566-9 20466882 RNA. 2010 Oct;16(10):1889-901 20801769 Mol Biol Rep. 2011 Feb;38(2):693-702 20369383 Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11 16341240 J Comput Biol. 2006 May;13(4):996-1003 16761924 Cancer Cell. 2006 Jun;9(6):435-43 16766263 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 Cell Cycle. 2007 Jul 1;6(13):1605-12 17534152 Cell Line, Tumor Colorectal Neoplasms genetics pathology DNA Methylation Epigenesis, Genetic Gene Expression Profiling Gene Silencing Humans MicroRNAs genetics PMC3116843 2011 1 24 2011 5 6 2011 6 16 2011 6 24 6 0 2011 6 24 6 0 2011 11 8 6 0 ppublish 10.1371/journal.pone.0020628 PONE-D-11-01853 21698188 PMC3116843 21665895 2011 08 04 2011 09 30 2013 11 21

1460-2180 32 8 2011 Aug Carcinogenesis MicroRNA 345, a methylation-sensitive microRNA is involved in cell proliferation and invasion in human colorectal cancer. 1207-15 10.1093/carcin/bgr114 Aberrant methylation has been shown to trigger the inactivation of tumor suppressor genes during tumorigenesis. MicroRNAs (miRNAs) have been found deregulated in human colorectal cancer (CRC), and some of them may function as tumor suppressor genes. Here, we investigated CpG island promoter hypermethylation as a potential mechanism underlying miRNA disruption and identifed methylation-sensitive miRNAs that might repress CRC development. We compared differential expression of miRNAs after 5-aza-2'-deoxycitidine (5-aza-dC) treatment using microarrays. DNA methylation status of the candidate miRNA was analyzed. The candidate miRNA was transfected into CRC cells and growth-suppressive mechanisms were explored. Luciferase reporter assay and western blot were used to identify the target genes of the candidate miRNA. The expression of mir-345 was significantly increased after 5-aza-dC treatment. DNA methylation analyses of mir-345 showed high methylation levels in tumor versus normal tissues. Expression of mir-345 was significantly down-regulated in 51.6% of CRC tissues compared with corresponding non-cancerous tissues. Low expression of mir-345 was associated with lymph node metastasis and worse histological type. Increased mir-345 function was sufficient to suppress colon cancer cell proliferation and invasiveness in vitro. Furthermore, we identified BCL2-associated athanogene 3 (BAG3), an anti-apoptosis protein, to be a target of mir-345. These results suggested as a methylation-sensitive miRNA in CRC, mir-345 may play an important role of antineoplastic as a growth inhibitor in the development of CRC. Tang Jie-Ting JT Digestive Department, Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine Renji Hospital, 145 Middle Shandong Road, Shanghai, China. Wang Ji-Lin JL Du Wan W Hong Jie J Zhao Shu-Liang SL Wang Ying-Chao YC Xiong Hua H Chen Hui-Min HM Fang Jing-Yuan JY eng Clinical Trial Journal Article Research Support, Non-U.S. Gov't 2011 06 10

England Carcinogenesis 8008055 0143-3334 0 Antimetabolites, Antineoplastic 0 DNA Primers 0 MIRN345 microRNA, human 0 MicroRNAs 0 RNA, Messenger 0 Tumor Markers, Biological 776B62CQ27 decitabine EC 1.13.12.- Luciferases M801H13NRU Azacitidine IM Adenocarcinoma genetics pathology Adult Aged Antimetabolites, Antineoplastic pharmacology Azacitidine analogs & derivatives pharmacology Blotting, Western Cell Movement Cell Proliferation Chromatin Immunoprecipitation Colorectal Neoplasms genetics pathology CpG Islands DNA Methylation DNA Primers Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Genes, bcl-2 Humans Immunoenzyme Techniques Luciferases metabolism Lymphatic Metastasis Male MicroRNAs physiology Middle Aged Neoplasm Invasiveness Oligonucleotide Array Sequence Analysis Prognosis Promoter Regions, Genetic genetics RNA, Messenger genetics Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Markers, Biological genetics metabolism 2011 6 10 2011 7 19 2011 6 14 6 0 2011 6 15 6 0 2011 10 1 6 0 ppublish bgr114 10.1093/carcin/bgr114 21665895 21533613 2011 09 28 2012 01 27 2013 11 21

1573-2568 56 10 2011 Oct Dig. Dis. Sci. Epigenetic silencing of microRNA-375 regulates PDK1 expression in esophageal cancer. 2849-56 10.1007/s10620-011-1711-1 MicroRNAs (miRNAs) are a class of small (19-25 nucleotides) noncoding RNAs that regulate the expressions of a wide variety of genes, including some involved in cancer development. Some recent studies show that DNA methylation contributes to down-regulation of microRNA-375 (miR-375) during tumorigenesis. Whether or not down-regulation of miR-375 also exists in esophageal cancer is unknown. Our aim was to test the hypothesis that down-regulation of miR-375 also exists in esophageal cancer. Expression of levels of miR-375 were examined using real-time PCR on paired esophageal cancer and adjacent non-cancerous tissues. The methylation status is detected by methylation specific-PCR (MSP). The results show that miR-375 is downregulated by hypermethylation of the promoter in esophageal cancer tissues. Epigenetic silencing of miR-375 induced an up-regulation of its targets, 3-phosphoinositide-dependent protein kinase-1 (PDK1). Restoration of the miR-375 expression in esophageal cancer cell lines downregulated the PDK1 expression. Furthermore, the miR-375 expression was found to be inversely correlated with PDK1 expression in esophageal cancer. Thus, miR-375 is frequently down-regulated in esophageal cancer and is a negative regulator of PDK1. Li Xiaoli X Department of Gerontology, The First Affiliated Hospital, Zhengzhou University, Institute of Clinical Medical Research of Universities in Henan Province, 1 East Jianshe Road, Zhengzhou, Henan Province, People's Republic of China. Lin Rui R Li Jiansheng J eng Journal Article 2011 04 30

United States Dig Dis Sci 7902782 0163-2116 0 DNA, Neoplasm 0 MIRN375 microRNA, human 0 MicroRNAs EC 2.7.11.1 3-Phosphoinositide-Dependent Protein Kinases EC 2.7.11.1 PDPK1 protein, human EC 2.7.11.1 Protein-Serine-Threonine Kinases AIM IM 3-Phosphoinositide-Dependent Protein Kinases Apoptosis physiology Carcinoma, Squamous Cell genetics metabolism pathology Cell Line, Tumor Cell Proliferation DNA Methylation physiology DNA, Neoplasm genetics Down-Regulation genetics physiology Epigenesis, Genetic genetics physiology Esophageal Neoplasms genetics metabolism pathology Gene Expression Regulation, Neoplastic genetics physiology Humans MicroRNAs genetics metabolism Protein-Serine-Threonine Kinases genetics metabolism Up-Regulation genetics physiology 2011 2 15 2011 4 5 2011 4 30 2011 5 3 6 0 2011 5 3 6 0 2012 1 28 6 0 ppublish 10.1007/s10620-011-1711-1 21533613 21516481 2011 05 12 2011 07 14 2014 04 08

1555-8932 6 2 2011 May Genes Nutr Epigenetic changes induced by curcumin and other natural compounds. 93-108 10.1007/s12263-011-0222-1 Epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression without any change in the DNA sequence, constitutes an important mechanism by which dietary components can selectively activate or inactivate gene expression. Curcumin (diferuloylmethane), a component of the golden spice Curcuma longa, commonly known as turmeric, has recently been determined to induce epigenetic changes. This review summarizes current knowledge about the effect of curcumin on the regulation of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. How these changes lead to modulation of gene expression is also discussed. We also discuss other nutraceuticals which exhibit similar properties. The development of curcumin for clinical use as a regulator of epigenetic changes, however, needs further investigation to determine novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents, for improving cancer treatment. Reuter Simone S Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Gupta Subash C SC Park Byoungduck B Goel Ajay A Aggarwal Bharat B BB eng P01 CA124787 CA NCI NIH HHS United States Journal Article 2011 04 24

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9069263 Thromb Haemost. 1997 Apr;77(4):772-82 9134658 Annu Rev Nutr. 2008;28:347-66 18598138 Carcinogenesis. 2008 Sep;29(9):1816-24 18628250 Clin Cancer Res. 2008 Jul 15;14(14):4491-9 18628464 Nutr Rev. 2008 Aug;66(8):477-82 18667010 Chin Med. 2008;3:11 18798984 Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17046-9 18955703 Biochem Biophys Res Commun. 2004 Apr 23;317(1):259-64 15047177 Cancer Res. 2004 Aug 15;64(16):5767-74 15313918 Org Biomol Chem. 2004 Oct 21;2(20):2902-10 15480453 Tumori. 1987 Feb 28;73(1):29-31 2435036 Int J Clin Pharmacol Ther Toxicol. 1986 Dec;24(12):651-4 3546166 Mol Cell Biochem. 1982 Feb 5;42(2):65-82 6174854 Indian J Med Res. 1980 Apr;71:632-4 7390600 Pharmazie. 2008 Oct;63(10):774-6 18972844 Trends Pharmacol Sci. 2009 Feb;30(2):85-94 19110321 Bioorg Med Chem Lett. 2009 Feb 1;19(3):706-9 19112019 Cancer Res. 2009 Jan 15;69(2):583-92 19147572 RNA Biol. 2008 Jul-Sep;5(3):115-9 19182522 J Pharmacol Exp Ther. 2009 May;329(2):505-14 19201992 Chem Biol. 2009 Feb 27;16(2):203-16 19246011 Eur J Med Chem. 2009 Jun;44(6):2711-9 19246131 PMC3092901 2011 2 1 2011 4 5 2011 4 24 2011 4 26 6 0 2011 4 26 6 0 2011 4 26 6 1 ppublish 10.1007/s12263-011-0222-1 21516481 PMC3092901 21515291 2011 11 07 2012 01 31

0027-5107 717 1-2 2011 Dec 1 Mutat. Res. microRNAs: implications for air pollution research. 38-45 10.1016/j.mrfmmm.2011.03.014 The purpose of this review is to provide an update of the current understanding on the role of microRNAs in mediating genetic responses to air pollutants and to contemplate on how these responses ultimately control susceptibility to ambient air pollution. Morbidity and mortality attributable to air pollution continues to be a growing public health concern worldwide. Despite several studies on the health effects of ambient air pollution, underlying molecular mechanisms of susceptibility and disease remain elusive. In the last several years, special attention has been given to the role of epigenetics in mediating, not only genetic and physiological responses to certain environmental insults, but also in regulating underlying susceptibility to environmental stressors. Epigenetic mechanisms control the expression of gene products, both basally and as a response to a perturbation, without affecting the sequence of DNA itself. These mechanisms include structural regulation of the chromatin structure, such as DNA methylation and histone modifications, and post-transcriptional gene regulation, such as microRNA mediated repression of gene expression. microRNAs are small noncoding RNAs that have been quickly established as key regulators of gene expression. As such, miRNAs have been found to control several cellular processes including apoptosis, proliferation and differentiation. More recently, research has emerged suggesting that changes in the expression of some miRNAs may be critical for mediating biological, and ultimately physiological, responses to air pollutants. Although the study of microRNAs, and epigenetics as a whole, has come quite far in the field of cancer, the understanding of how these mechanisms regulate gene-environment interactions to environmental exposures in everyday life is unclear. This article does not necessarily reflect the views and policies of the US EPA. Published by Elsevier B.V. Jardim Melanie J MJ National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Chapel Hill, NC, USA. melaniejardim@gmail.com eng Journal Article Review 2011 04 14

Netherlands Mutat Res 0400763 0027-5107 0 Air Pollutants 0 MicroRNAs IM Air Pollutants toxicity Air Pollution adverse effects Animals Epigenesis, Genetic drug effects Gene Expression Regulation drug effects Humans MicroRNAs genetics metabolism Research 2010 9 10 2011 3 22 2011 3 31 2011 4 14 2011 4 26 6 0 2011 4 26 6 0 2012 2 1 6 0 ppublish S0027-5107(11)00080-7 10.1016/j.mrfmmm.2011.03.014 21515291 21383543 2011 03 08 2011 09 14

1555-8576 11 5 2011 Mar 1 Cancer Biol. Ther. DNA hypermethylation of microRNA-34b/c has prognostic value for stage Ⅰ non-small cell lung cancer. 490-6 10.4161/cbt.11.5.14550 Lung cancer is the leading cause of cancer-related death in the world and approximately 30-40% of patients with stage Ⅰ non-small cell lung cancer (NSCLC) die of recurrent disease. miRNA expression profiles can be diagnostic and prognostic markers of lung cancer. Recently, miR-34 family has been shown to be part of the p53 pathway which is frequently involved in lung cancer, and the expression of miR-34 has been reported to be regulated by DNA methylation. In present study, we investigated the correlation between DNA methylation status of miR-34 family and recurrence of stage Ⅰ NSCLC patients. miR-34a and miR-34b/c promoter methylation status were determined by nested methylation-specific PCR in FFPE tumor tissues from 161 patients of stage Ⅰ NSCLC. Furthermore, mature miR-34b and miR-34c expression were analyzed by qRT-PCR in the same panel tissues. Our results revealed that aberrant DNA methylation of miR-34b/c was correlated with a high probability of recurrence (p = 0.026) and associated with poor overall survival (p = 0.010) and disease-free survival (p = 0.017). No significant association was found for miR-34a methylation. Multivariate analysis showed that promoter hypermethylation of miR-34b/c was an independent prognostic factor of stage Ⅰ NSCLC. Moreover, no significant association between mature miR-34b and miR-34c expression and DNA methylation status was found. In conclusion, we have identified promoter hypermethylation of miR-34b/c as a relatively common event in NSCLC and might be a potential prognostic factor for stage Ⅰ NSCLC. Wang Zhen Z Department of Thoracic Surgery, Peking Union Medical College and Chinese Academy of Medical Sciences, China. Chen Zhaoli Z Gao Yushun Y Li Ning N Li Baozhong B Tan Fengwei F Tan Xiaogang X Lu Ning N Sun Yuntian Y Sun Jian J Sun Nan N He Jie J eng Journal Article Research Support, Non-U.S. Gov't

United States Cancer Biol Ther 101137842 1538-4047 0 MIRN34 microRNA, human 0 MicroRNAs IM Carcinoma, Non-Small-Cell Lung genetics pathology therapy DNA Methylation Disease-Free Survival Female Gene Expression Humans Lung Neoplasms genetics pathology therapy Male MicroRNAs genetics Neoplasm Recurrence, Local Polymerase Chain Reaction Prognosis Promoter Regions, Genetic Retrospective Studies 2011 3 9 6 0 2011 3 9 6 0 2011 9 15 6 0 ppublish 14550 10.4161/cbt.11.5.14550 21383543 21352815 2011 03 28 2011 05 24 2013 11 21

1090-2104 406 4 2011 Mar 25 Biochem. Biophys. Res. Commun. Down-regulation of NDRG2 gene expression in human colorectal cancer involves promoter methylation and microRNA-650. 534-8 10.1016/j.bbrc.2011.02.081 The expression of N-myc downstream-regulated gene 2 (NDRG2) is present in normal tissues but low or undetectable in various cancers and thus poses a potential tumor suppressor gene. However, the expression of NDRG2 in colorectal tissues remains unknown. Here, our results showed that NDRG2 was down-regulated in colorectal cancer compared to benign colorectal tissues by using immunohistochemical staining and semi-quantitative RT-PCR analyses. Bisulfite sequencing analysis showed that the reduced NDRG2 expression was accompanied by de novo DNA methylation at the NDRG2 promoter. We also found that microRNA-650 (miR-650) targets a homologous DNA region in the promoter region of the NDRG2 gene and represses its expression at the transcriptional level. Reporter assay with 3'untranslated region of NDRG2 cloned downstream of the luciferase gene showed reduced luciferase activity in the presence of miR-650, providing strong evidence that miR-650 is a direct regulator of NDRG2. In conclusion, these results suggest that NDRG2 expression is regulated by promoter methylation and miR-650 in human colorectal cancer cells, and endogenous small noncoding RNA induced control of transcription may be a potential system for expressional regulation in human colorectal cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved. Feng Li L Department of Gastroenterology, Minhang District Central Hospital, Shanghai, China. Xie Yun Y Zhang Hao H Wu Yunlin Y eng Journal Article Research Support, Non-U.S. Gov't 2011 02 23

United States Biochem Biophys Res Commun 0372516 0006-291X 0 Antimetabolites, Antineoplastic 0 MIRN650 microRNA, human 0 MicroRNAs 0 NDRG2 protein, human 0 Tumor Suppressor Proteins M801H13NRU Azacitidine IM Antimetabolites, Antineoplastic pharmacology Azacitidine pharmacology Carcinoma genetics secondary Cell Line, Tumor Colorectal Neoplasms genetics pathology DNA Methylation Down-Regulation Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics metabolism Molecular Sequence Data Promoter Regions, Genetic Tumor Suppressor Proteins genetics 2011 2 10 2011 2 16 2011 2 23 2011 3 1 6 0 2011 3 1 6 0 2011 5 25 6 0 ppublish S0006-291X(11)00286-5 10.1016/j.bbrc.2011.02.081 21352815 21349819 2011 05 04 2011 07 07 2013 10 18

1460-2180 32 5 2011 May Carcinogenesis MicroRNA-145 is regulated by DNA methylation and p53 gene mutation in prostate cancer. 772-8 10.1093/carcin/bgr036 MiR-145 is downregulated in various cancers including prostate cancer. However, the underlying mechanisms of miR-145 downregulation are not fully understood. Here, we reported that miR-145 was silenced through DNA hypermethylation and p53 mutation status in laser capture microdissected (LCM) prostate cancer and matched adjacent normal tissues. In 22 of 27 (81%) prostate tissues, miR-145 was significantly downregulated in the cancer compared with the normal tissues. Further studies on miR-145 downregulation mechanism showed that miR-145 is methylated at the promoter region in both prostate cancer tissues and 50 different types of cancer cell lines. In seven cancer cell lines with miR-145 hypermethylation, 5-aza-2'-deoxycytidine treatment dramatically induced miR-145 expression. Interestingly, we also found a significant correlation between miR-145 expression and the status of p53 gene in both LCM prostate tissues and 47 cancer cell lines. In 29 cell lines with mutant p53, miR-145 levels were downregulated in 28 lines (97%), whereas in 18 cell lines with wild-type p53 (WT p53), miR-145 levels were downregulated in only 6 lines (33%, P < 0.001). Electrophoretic mobility shift assay showed that p53 binds to the p53 response element upstream of miR-145, but the binding was inhibited by hypermethylation. To further confirm that p53 binding to miR-145 could regulate miR-145 expression, we transfected WT p53 and MUT p53 into PC-3 cells and found that miR-145 is upregulated by WT p53 but not with MUTp53. The apoptotic cells are increased after WT p53 transfection. In summary, this is the first report documenting that downregulation of miR-145 is through DNA methylation and p53 mutation pathways in prostate cancer. Suh Seong O SO Department of Urology, Veterans Affairs Medical Center and University of California at San Francisco, 4150 Clement Street, San Francisco, CA 94121, USA. Chen Yi Y Zaman Mohd Saif MS Hirata Hiroshi H Yamamura Soichiro S Shahryari Varahram V Liu Jan J Tabatabai Z Laura ZL Kakar Sanjay S Deng Guoren G Tanaka Yuichiro Y Dahiya Rajvir R eng R01CA138642-01 CA NCI NIH HHS United States T32DK007790 DK NIDDK NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2011 02 23

England Carcinogenesis 8008055 0143-3334 0 MIRN145 microRNA, human 0 MicroRNAs 0 RNA, Messenger 0 TP53 protein, human 0 Tumor Suppressor Protein p53 IM Science. 2001 Oct 26;294(5543):853-8 11679670 Cancer Res. 2010 Apr 1;70(7):2728-38 20332243 Mol Cancer Res. 2003 Oct;1(12):882-91 14573789 J Clin Oncol. 2004 Jul 15;22(14):2790-9 15254046 Nature. 1997 May 15;387(6630):296-9 9153395 Nature. 1997 May 15;387(6630):299-303 9153396 BMC Cancer. 2005 Jan 20;5:9 15661074 BMC Cancer. 2005;5:45 15892885 Cancer Res. 2005 Aug 15;65(16):7065-70 16103053 Nat Rev Cancer. 2006 Jan;6(1):83-90 16397528 J Cell Biochem. 2006 Feb 15;97(3):433-47 16267836 Cell Cycle. 2007 May 2;6(9):1001-5 17457051 Cell Cycle. 2007 Jun 15;6(12):1455-9 17581274 Cancer Res. 2007 Jul 1;67(13):6130-5 17616669 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 Cancer Sci. 2007 Dec;98(12):1914-20 17892514 J Biol Chem. 2007 Nov 9;282(45):32582-90 17827156 Cancer Cell. 2007 Nov;12(5):414-8 17996645 Prostate. 2008 Feb 1;68(2):152-60 18058812 Oncogene. 2008 Mar 13;27(12):1788-93 17891175 Methods Mol Biol. 2007;407:97-114 18453251 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Cell Cycle. 2008 Aug 15;7(16):2591-600 18719384 J Clin Endocrinol Metab. 2009 Jan;94(1):320-3 18840638 Clin Cancer Res. 2009 Feb 15;15(4):1177-83 19228723 Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3207-12 19202062 Cell. 2009 May 15;137(4):647-58 19409607 Int J Cancer. 2009 Jul 15;125(2):345-52 19378336 Nature. 2009 Aug 6;460(7256):705-10 19578358 Clin Cancer Res. 2009 Aug 15;15(16):5073-81 19671867 Cancer Res. 2009 Dec 15;69(24):9490-7 19996289 Int J Cancer. 2010 Mar 1;126(5):1166-76 19676045 Cancer Res. 2010 Jan 1;70(1):378-87 19996288 Cell Death Differ. 2010 Feb;17(2):373-5 20062068 Clin Cancer Res. 2010 Feb 15;16(4):1119-28 20145172 Nature. 2002 Oct 17;419(6908):729-34 12384701 Apoptosis Chromatin Immunoprecipitation DNA Methylation Electrophoretic Mobility Shift Assay Humans In Situ Hybridization Lasers Male MicroRNAs genetics Microdissection Mutation genetics Promoter Regions, Genetic genetics Prostate metabolism pathology Prostatic Hyperplasia genetics pathology Prostatic Neoplasms genetics pathology RNA, Messenger genetics Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Suppressor Protein p53 genetics PMC3086703 2011 2 23 2011 2 26 6 0 2011 2 26 6 0 2011 7 8 6 0 ppublish bgr036 10.1093/carcin/bgr036 21349819 PMC3086703 21255435 2011 02 11 2011 04 19 2013 10 20

1471-2164 12 2011 BMC Genomics Discovery pipeline for epigenetically deregulated miRNAs in cancer: integration of primary miRNA transcription. 54 10.1186/1471-2164-12-54 Cancer is commonly associated with widespread disruption of DNA methylation, chromatin modification and miRNA expression. In this study, we established a robust discovery pipeline to identify epigenetically deregulated miRNAs in cancer. Using an integrative approach that combines primary transcription, genome-wide DNA methylation and H3K9Ac marks with microRNA (miRNA) expression, we identified miRNA genes that were epigenetically modified in cancer. We find miR-205, miR-21, and miR-196b to be epigenetically repressed, and miR-615 epigenetically activated in prostate cancer cells. We show that detecting changes in primary miRNA transcription levels is a valuable method for detection of local epigenetic modifications that are associated with changes in mature miRNA expression. Hulf Toby T Epigenetics Laboratory, Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Sibbritt Tennille T Wiklund Erik D ED Bert Saul S Strbenac Dario D Statham Aaron L AL Robinson Mark D MD Clark Susan J SJ eng Journal Article Research Support, Non-U.S. Gov't 2011 01 21

England BMC Genomics 100965258 1471-2164 0 MicroRNAs IM Int J Cancer. 2010 Sep 1;127(5):1072-80 20039318 Mol Cell. 2010 May 14;38(3):323-32 20471939 Haematologica. 2010 Oct;95(10):1675-82 20494936 Int J Cancer. 2011 Jan 1;128(1):132-43 20309880 Genome Res. 2010 Dec;20(12):1719-29 21045081 Int J Cancer. 2011 Mar 15;128(6):1327-34 20473948 Epigenomics. 2010 Dec;2(6):823-40 22122085 Oncogene. 2002 Feb 7;21(7):1048-61 11850822 Cancer Res. 2003 May 1;63(9):2164-71 12727835 Nature. 2004 May 27;429(6990):457-63 15164071 Cancer Res. 2004 Jun 1;64(11):3871-7 15172996 Cell Cycle. 2006 Jan;5(2):155-8 16397413 Genes Dev. 2006 Aug 15;20(16):2202-7 16882971 Hum Genet. 2007 Jan;120(5):701-11 17024368 Int J Cancer. 2007 Mar 1;120(5):1046-54 17149698 Pathology. 2007 Jun;39(3):299-304 17558856 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 RNA. 2008 Jan;14(1):35-42 18025253 Blood. 2008 Feb 1;111(3):1217-26 17957028 Oncogene. 2008 Mar 13;27(12):1788-93 17891175 Nat Rev Genet. 2008 Oct;9(10):789-96 18781158 Int J Biochem Cell Biol. 2009 Jan;41(1):87-95 18834952 Br J Cancer. 2009 Jan 27;100(2):240-5 19002169 PLoS One. 2009;4(3):e4687 19262738 Cancer Res. 2009 Mar 15;69(6):2287-95 19244118 Clin Chem. 2009 Apr;55(4):623-31 19246618 Blood. 2009 Apr 2;113(14):3314-22 19188669 Curr Opin Cell Biol. 2009 Jun;21(3):470-9 19411171 Cell. 2009 Jun 12;137(6):1032-46 19524507 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 PLoS One. 2009;4(11):e7826 19915715 BMC Cancer. 2009;9:401 19922656 Int J Cancer. 2010 Mar 1;126(5):1166-76 19676045 PLoS One. 2010;5(1):e8697 20084174 Nucleic Acids Res. 2010 Jan;38(2):391-9 19906696 Clin Cancer Res. 2010 Feb 15;16(4):1129-39 20145181 Mol Cancer. 2010;9:12 20092645 Nat Cell Biol. 2010 Mar;12(3):235-46 20173741 PLoS One. 2010;5(2):e9429 20195546 Int J Cancer. 2010 Jun 1;126(11):2553-62 19830692 Cell Cycle. 2010 Mar 1;9(5):923-9 20160498 Nat Rev Cancer. 2010 May;10(5):361-71 20357775 Am J Pathol. 2010 May;176(5):2113-30 20348243 Genes Chromosomes Cancer. 2010 Nov;49(11):969-80 20662076 Cell Line, Tumor Epigenesis, Genetic genetics Gene Expression Regulation, Neoplastic genetics Humans MicroRNAs genetics Neoplasms genetics PMC3037319 2010 5 26 2011 1 21 2011 1 21 2011 1 25 6 0 2011 1 25 6 0 2011 4 20 6 0 epublish 1471-2164-12-54 10.1186/1471-2164-12-54 21255435 PMC3037319 21221794 2011 06 13 2011 08 17

1573-2568 56 7 2011 Jul Dig. Dis. Sci. miR-137 is frequently down-regulated in gastric cancer and is a negative regulator of Cdc42. 2009-16 10.1007/s10620-010-1536-3 MicroRNAs (miRNAs) are a class of small (19-25 nucleotides) noncoding RNAs that regulate the expressions of a wide variety of genes, including some involved in cancer development. Some recent studies show that DNA methylation contributes to down-regulation of microRNA-137 (miR-137) during tumorigenesis. Whether down-regulation of miR-137 also exists in gastric cancer is unknown. Our aim was to test the hypothesis that down-regulation of miR-137 also exists in gastric cancer. Expression of levels of miR-137 were examined using real-time PCR on paired gastric cancer and adjacent non-cancerous tissues. The methylation status is detected by MSP. Results show that miR-137 is downregulated by hypermethylation of the promoter in gastric cancer tissues. Epigenetic silencing of miR-137 induced an up-regulation of its targets, Cdc42. Restoration of the miR-137 expression in gastric cancer cell lines downregulated the Cdc42 expression. Restoration of the miR-137 and inactivation of Cdc42 induce apoptosis and cell cycle G1 arrest in gastric cancer cells. Furthermore, the miR-137 expression was found to be inversely correlated with CDC42 expression in gastric caner. miR-137 is frequently down-regulated in gastric cancer and is a negative regulator of Cdc42. Chen Qingjiang Q Department of Medicine-Oncology, The First Affiliated Hospital, Zhengzhou University, 1 East Jianshe Road, 450000, Zhengzhou, People's Republic of China. Chen Xiaobing X Zhang Mingzhi M Fan Qingxia Q Luo Suxia S Cao Xinguang X eng Journal Article 2011 01 08

United States Dig Dis Sci 7902782 0163-2116 0 MIRN137 microRNA, human 0 MicroRNAs EC 3.6.5.2 cdc42 GTP-Binding Protein AIM IM Base Sequence Carcinoma metabolism Cell Line, Tumor DNA Methylation Down-Regulation Gene Expression Regulation, Neoplastic Gene Silencing Humans MicroRNAs biosynthesis Molecular Sequence Data Stomach Neoplasms metabolism cdc42 GTP-Binding Protein biosynthesis metabolism 2010 10 6 2010 12 16 2011 1 8 2011 1 12 6 0 2011 1 12 6 0 2011 8 19 6 0 ppublish 10.1007/s10620-010-1536-3 21221794 21159317 2011 02 02 2011 05 17 2013 11 21

0027-5107 707 1-2 2011 Feb 10 Mutat. Res. Radiation-induced epigenetic alterations after low and high LET irradiations. 24-33 10.1016/j.mrfmmm.2010.12.003 Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding radiation-induced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGI, and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET X-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NFκB), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. We demonstrate that miRNA expression levels can be altered after X-ray irradiation and that these miRNA are involved in chromatin remodeling and DNA methylation. A higher incidence of epigenetic changes was observed after exposure to X-rays than Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This distinction is apparent at miRNA analyses at which only three miRNA involved in two major pathways were altered after high LET irradiations while six miRNA involved in five major pathways were altered after low LET irradiations. This study also shows that the irradiated cells acquire epigenetic changes suggesting that epigenetic aberrations may arise in the cell without initiating chromosomal instability. Copyright © 2010 Elsevier B.V. All rights reserved. Aypar Umut U Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. uaypa001@umaryland.edu Morgan William F WF Baulch Janet E JE eng Journal Article Research Support, U.S. Gov't, Non-P.H.S. 2010 12 13

Netherlands Mutat Res 0400763 0027-5107 0 Ions 0 MicroRNAs E1UOL152H7 Iron IM Animals Cell Line Cell Survival radiation effects Cricetinae DNA Damage radiation effects DNA Methylation radiation effects Dose-Response Relationship, Radiation Epigenesis, Genetic radiation effects Genomic Instability radiation effects Humans Ions Iron Linear Energy Transfer MicroRNAs radiation effects X-Rays 2010 10 14 2010 12 6 2010 12 6 2010 12 13 2010 12 17 6 0 2010 12 17 6 0 2011 5 18 6 0 ppublish S0027-5107(10)00310-6 10.1016/j.mrfmmm.2010.12.003 21159317 21149325 2010 12 14 2011 04 05 2014 09 12

1940-6215 3 12 2010 Dec Cancer Prev Res (Phila) Linking epidemiology to epigenomics--where are we today? 1505-8 10.1158/1940-6207.CAPR-10-0298 Cancer is the consequence of genetic and epigenetic alterations. Genetic mutations likely result in part from exposure to environmental carcinogens, giving rise to a large field of cancer-prevention study of these carcinogens and ways to develop strategies to avoid them. Our understanding of regulatory epigenetic mechanisms associated with DNA methylation, histone modifications, and microRNA production is increasing rapidly. The involvement of these processes in carcinogenesis raises the possibility that environmental exposures may promote or prevent cancer through affecting the epigenome. Modifying the epigenome to prevent cancer is particularly intriguing because epigenetic alterations are potentially reversible, unlike gene mutations, and because certain dietary factors, such as the B-vitamin folate, may affect genes' DNA methylation status (as reported by Wallace et al., beginning on page 1552 in this issue of the journal). Rapidly improving techniques for assessing epigenetic alterations promise to yield important insights for cancer prevention. ©2010 AACR. Ulrich Cornelia M CM National Center for Tumor Diseases Heidelberg (NCT), Division of Preventive Oncology, Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany. neli.ulrich@nct-heidelberg.de Grady William M WM eng R01 CA 112516 CA NCI NIH HHS United States R01 CA 114467 CA NCI NIH HHS United States R01 CA 120523 CA NCI NIH HHS United States R01 CA105437 CA NCI NIH HHS United States R01 CA105437-04 CA NCI NIH HHS United States R01 CA112516 CA NCI NIH HHS United States R01 CA112516-05S1 CA NCI NIH HHS United States R01 CA114467 CA NCI NIH HHS United States R01 CA114467-05 CA NCI NIH HHS United States R01 CA120523 CA NCI NIH HHS United States R01 CA120523-04 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

United States Cancer Prev Res (Phila) 101479409 1940-6215 IM Environ Mol Mutagen. 2004;44(1):10-25 15199543 Am J Clin Nutr. 2000 Oct;72(4):998-1003 11010943 Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8681-6 10411935 Nat Rev Cancer. 2004 Dec;4(12):988-93 15573120 Int J Cancer. 2005 Mar 20;114(2):219-23 15540210 Gut. 2005 May;54(5):648-53 15831910 Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10604-9 16009939 Semin Oncol. 2005 Oct;32(5):521-30 16210093 J Nutr. 2005 Nov;135(11):2698-702 16251633 Science. 2005 Dec 16;310(5755):1761 16357241 Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):189-93 16492904 Nat Genet. 2006 Jul;38(7):787-93 16804544 Gut. 2006 Oct;55(10):1387-9 16966698 Cancer Epidemiol Biomarkers Prev. 2007 Feb;16(2):327-33 17301267 JAMA. 2007 Jun 6;297(21):2351-9 17551129 Cancer Epidemiol Biomarkers Prev. 2000 Aug;9(8):849-53 10952104 J Natl Cancer Inst. 2009 Mar 18;101(6):432-5 19276452 Cancer Res. 2002 Apr 15;62(8):2370-7 11956099 J Natl Cancer Inst. 2002 May 15;94(10):755-61 12011226 Cancer Res. 2003 Jul 1;63(13):3743-6 12839968 Mol Cell Biol. 2003 Aug;23(15):5293-300 12861015 Nutr Rev. 2009 Apr;67(4):206-12 19335714 Nat Biotechnol. 2009 Apr;27(4):341-2 19352369 Cancer Prev Res (Phila). 2010 Dec;3(12):1552-64 21149331 Carcinogenesis. 2004 Jun;25(6):1063-7 14742312 JAMA. 2007 Jun 6;297(21):2408-9 17551134 Am J Clin Nutr. 2007 Aug;86(2):271-3 17684194 Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13056-61 17670942 Carcinogenesis. 2007 Aug;28(8):1672-9 17449906 Cancer Epidemiol Biomarkers Prev. 2007 Dec;16(12):2526-32 18086755 Cancer Epidemiol Biomarkers Prev. 2008 Feb;17(2):330-8 18268116 N Engl J Med. 2008 Mar 13;358(11):1148-59 18337604 Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2220-5 18768486 Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2226-30 18768487 J Nutr Biochem. 2004 Sep;15(9):554-60 15350988 DNA Methylation Epigenesis, Genetic Epigenomics Humans Neoplasms epidemiology genetics NIHMS249484 PMC3048787 2010 12 15 6 0 2010 12 15 6 0 2011 4 6 6 0 ppublish 3/12/1505 10.1158/1940-6207.CAPR-10-0298 21149325 PMC3048787 NIHMS249484 21074720 2010 11 15 2010 12 23

1878-1551 19 5 2010 Nov 16 Dev. Cell Aberrant epigenetic landscape in cancer: how cellular identity goes awry. 698-711 10.1016/j.devcel.2010.10.005 Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed. Copyright © 2010 Elsevier Inc. All rights reserved. Berdasco María M Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, 08907 Barcelona, Catalonia, Spain. Esteller Manel M eng Journal Article Review

United States Dev Cell 101120028 1534-5807 0 Histones 0 MicroRNAs IM Animals Cell Differentiation genetics DNA Methylation Embryonic Development genetics Epigenesis, Genetic Epigenomics Genomic Imprinting Genomic Instability Histones genetics metabolism Humans MicroRNAs genetics metabolism Neoplasms genetics therapy X Chromosome Inactivation 2010 11 16 6 0 2010 11 16 6 0 2010 12 25 6 0 ppublish S1534-5807(10)00458-2 10.1016/j.devcel.2010.10.005 21074720 21057533 2011 03 17 2011 05 19

1476-5594 30 11 2011 Mar 17 Oncogene Chromosomal, epigenetic and microRNA-mediated inactivation of LRP1B, a modulator of the extracellular environment of thyroid cancer cells. 1302-17 10.1038/onc.2010.512 The low-density lipoprotein receptor-related protein (LRP1B), encoding an endocytic LDL-family receptor, is among the 10 most significantly deleted genes across 3312 human cancer specimens. However, currently the apparently crucial role of this lipoprotein receptor in carcinogenesis is not clear. Here we show that LRP1B inactivation (by chromosomal, epigenetic and microRNA (miR)-mediated mechanisms) results in changes to the tumor environment that confer cancer cells an increased growth and invasive capacity. LRP1B displays frequent DNA copy number loss and CpG island methylation, resulting in mRNA underexpression. By using CpG island reporters methylated in vitro, we found that DNA methylation disrupts a functional binding site for the histone-acetyltransferase p300 located at intron 1. We identified and validated an miR targeting LRP1B (miR-548a-5p), which is overexpressed in cancer cell lines as a result of 8q22 DNA gains. Restoration of LRP1B impaired in vitro and in vivo tumor growth, inhibited cell invasion and led to a reduction of matrix metalloproteinase 2 in the extracellular medium. We emphasized the role of an endocytic receptor acting as a tumor suppressor by modulating the extracellular environment composition in a way that constrains the invasive behavior of the cancer cells. Prazeres H H Department of Cancer Biology, Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal. Torres J J Rodrigues F F Pinto M M Pastoriza M C MC Gomes D D Cameselle-Teijeiro J J Vidal A A Martins T C TC Sobrinho-Simões M M Soares P P eng Journal Article Research Support, Non-U.S. Gov't 2010 11 08

England Oncogene 8711562 0950-9232 0 MicroRNAs 0 RNA, Messenger 0 Receptors, LDL EC 3.4.24.24 Matrix Metalloproteinase 2 IM Cell Line, Tumor CpG Islands DNA Methylation Epigenesis, Genetic Gene Silencing Gene Targeting Genes, Tumor Suppressor Humans Matrix Metalloproteinase 2 genetics metabolism MicroRNAs genetics metabolism physiology Neoplasm Invasiveness RNA, Messenger genetics metabolism Receptors, LDL chemistry genetics metabolism Reproducibility of Results Thyroid Neoplasms genetics 2010 11 08 2010 11 9 6 0 2010 11 9 6 0 2011 5 20 6 0 ppublish onc2010512 10.1038/onc.2010.512 21057533 20959400 2010 11 15 2010 12 17

1542-4863 60 6 2010 Nov-Dec CA Cancer J Clin Cancer epigenetics. 376-92 10.3322/caac.20085 Epigenetics refers to stable alterations in gene expression with no underlying modifications in the genetic sequence and is best exemplified by differentiation, in which multiple cell types diverge physiologically despite a common genetic code. Interest in this area of science has grown over the past decades, especially since it was found to play a major role in physiologic phenomena such as embryogenesis, imprinting, and X chromosome inactivation, and in disease states such as cancer. The latter had been previously thought of as a disease with an exclusive genetic etiology. However, recent data have demonstrated that the complexity of human carcinogenesis cannot be accounted for by genetic alterations alone, but also involves epigenetic changes in processes such as DNA methylation, histone modifications, and microRNA expression. In turn, these molecular alterations lead to permanent changes in the expression of genes that regulate the neoplastic phenotype, such as cellular growth and invasiveness. Targeting epigenetic modifiers has been referred to as epigenetic therapy. The success of this approach in hematopoietic malignancies validates the importance of epigenetic alterations in cancer, not only at the therapeutic level but also with regard to prevention, diagnosis, risk stratification, and prognosis. © 2010 American Cancer Society, Inc. Taby Rodolphe R Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. Issa Jean-Pierre J JP eng Journal Article Research Support, Non-U.S. Gov't Review 2010 10 19

United States CA Cancer J Clin 0370647 0007-9235 0 Histones 0 MicroRNAs 0 Tumor Markers, Biological AIM IM Animals Cell Cycle genetics Cell Transformation, Neoplastic genetics DNA Methylation Epigenesis, Genetic Histones genetics Humans MicroRNAs genetics Neoplasm Invasiveness genetics Neoplasms classification diagnosis genetics metabolism prevention & control therapy Prognosis Risk Assessment Tumor Markers, Biological genetics 2010 10 19 2010 10 21 6 0 2010 10 21 6 0 2010 12 18 6 0 ppublish caac.20085 10.3322/caac.20085 20959400 20933131 2010 10 11 2010 11 10

0065-2660 71 2010 Adv. Genet. Diet, epigenetic, and cancer prevention. 237-55 10.1016/B978-0-12-380864-6.00008-0 Disruption of the epigenome has been a hallmark of human cancers and has been linked with tumor pathogenesis and progression. Since epigenetic changes can be reversed in principle, studies have been carried out to identify modifiable (such as diet and lifestyle) factors, which possess epigenetic property, in hope for developing epigenetically based prevention/intervention strategies. The goal is to achieve some degree of epigenetic reprogramming, which would maintain normal gene expression status and reverse tumorigenesis through chemoprevention or lifestyle intervention such as diet modification. The ability of dietary compounds to act epigenetically in cancer cells has been studied and evidence continues to surface for constituents in food and dietary supplements to influence the epigenome and ultimately individual's risk of developing cancer. In this chapter, we summarized the existing data, both from animal and human studies, on the capacity of natural food products to influence three key epigenetic processes: DNA methylation, histone modification, and microRNA expression. As discussed in the perspective, while diet-based intervention that targets epigenetic pathways is promising, significant challenges remain in translating these scientific findings into clinical or public health practices in the context of cancer prevention. Copyright © 2010 Elsevier Inc. All rights reserved. Chen Jia J Department of Preventive Medicine, Mount Sinai School of Medicine,New York, USA. Xu Xinran X eng 3R01CA109753-04S1 CA NCI NIH HHS United States R01 CA109753 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Review

United States Adv Genet 0370421 0065-2660 0 Histones 0 MicroRNAs IM Animals Clinical Trials as Topic DNA Methylation Diet Epigenesis, Genetic Gene Expression Regulation, Neoplastic Histones metabolism Humans MicroRNAs metabolism Neoplasms genetics prevention & control 2010 10 12 6 0 2010 10 12 6 0 2010 11 11 6 0 ppublish B978-0-12-380864-6.00008-0 10.1016/B978-0-12-380864-6.00008-0 20933131 20933124 2010 10 11 2010 11 10 2014 02 20

0065-2660 71 2010 Adv. Genet. Induction of epigenetic alterations by dietary and other environmental factors. 3-39 10.1016/B978-0-12-380864-6.00001-8 Dietary and other environmental factors induce epigenetic alterations which may have important consequences for cancer development. This chapter summarizes current knowledge of the impact of dietary, lifestyle, and environmental determinants of cancer risk and proposes that effects of these exposures might be mediated, at least in part, via epigenetic mechanisms. Evidence is presented to support the hypothesis that all recognized epigenetic marks (including DNA methylation, histone modification, and microRNA (miRNA) expression) are influenced by environmental exposures, including diet, tobacco, alcohol, physical activity, stress, environmental carcinogens, genetic factors, and infectious agents which play important roles in the etiology of cancer. Some of these epigenetic modifications change the expression of tumor suppressor genes and oncogenes and, therefore, may be causal for tumorigenesis. Further work is required to understand the mechanisms through which specific environmental factors produce epigenetic changes and to identify those changes which are likely to be causal in the pathogenesis of cancer and those which are secondary, or bystander, effects. Given the plasticity of epigenetic marks in response to cancer-related exposures, such epigenetic marks are attractive candidates for the development of surrogate endpoints which could be used in dietary or lifestyle intervention studies for cancer prevention. Future research should focus on identifying epigenetic marks which are (i) validated as biomarkers for the cancer under study; (ii) readily measured in easily accessible tissues, for example, blood, buccal cells, or stool; and (iii) altered in response to dietary or lifestyle interventions for which there is convincing evidence for a relationship with cancer risk. Copyright © 2010 Elsevier Inc. All rights reserved. Mathers John C JC Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom. Strathdee Gordon G Relton Caroline L CL eng BH071163 Biotechnology and Biological Sciences Research Council United Kingdom BH081097 Biotechnology and Biological Sciences Research Council United Kingdom BH090948 Biotechnology and Biological Sciences Research Council United Kingdom G0601333 Medical Research Council United Kingdom Medical Research Council United Kingdom Journal Article Research Support, Non-U.S. Gov't Review

United States Adv Genet 0370421 0065-2660 0 Biological Markers IM Biological Markers DNA Methylation Diet adverse effects Environmental Exposure adverse effects Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans Neoplasms chemically induced genetics Nutrigenomics Risk Factors 2010 10 12 6 0 2010 10 12 6 0 2010 11 11 6 0 ppublish B978-0-12-380864-6.00001-8 10.1016/B978-0-12-380864-6.00001-8 20933124 20926598 2010 12 28 2011 06 01 2013 10 21

1460-2423 21 2 2011 Feb Glycobiology DNA methylation and histone H3-K9 modifications contribute to MUC17 expression. 247-56 10.1093/glycob/cwq155 MUC17 glycoprotein is a membrane-associated mucin that is mainly expressed in the digestive tract. It has been suggested that MUC17 expression is correlated with the malignancy potential of pancreatic ductal adenocarcinomas (PDACs). In the present study, we provided the first report of the MUC17 gene expression through epigenetic regulation such as promoter methylation, histone modification and microRNA (miRNA) expression. Near the transcriptional start site, the DNA methylation level of MUC17-negative cancer cell lines (e.g. PANC1) was high, whereas that of MUC17-positive cells (e.g. AsPC-1) was low. Histone H3-K9 (H3-K9) modification status was also closely related to MUC17 expression. Our results indicate that DNA methylation and histone H3-K9 modification in the 5' flanking region play a critical role in MUC17 expression. Furthermore, the hypomethylation status was observed in patients with PDAC. This indicates that the hypomethylation status in the MUC17 promoter could be a novel epigenetic marker for the diagnosis of PDAC. In addition, the result of miRNA microarray analysis showed that five potential miRNA candidates existed. It is also possible that the MUC17 might be post-transcriptionally regulated by miRNA targeting to the 3'-untranslated region of its mRNA. These understandings of the epigenetic changes of MUC17 may be of importance for the diagnosis of carcinogenic risk and the prediction of outcomes for cancer patients. Kitamoto Sho S Department of Human Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan. Yamada Norishige N Yokoyama Seiya S Houjou Izumi I Higashi Michiyo M Goto Masamichi M Batra Surinder K SK Yonezawa Suguru S eng R01 CA78590 CA NCI NIH HHS United States U01CA111294 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010 10 06

England Glycobiology 9104124 0959-6658 0 3' Untranslated Regions 0 DNA, Neoplasm 0 Histones 0 MUC17 protein, human 0 MicroRNAs 0 Mucins 0 RNA, Messenger 0 Tumor Markers, Biological EC 3.5.1.98 Histone Deacetylases IM Biochem Biophys Res Commun. 2002 Mar 1;291(3):466-75 11855812 J Hepatobiliary Pancreat Sci. 2010 Nov;17(6):844-54 20734208 Oncogene. 2002 Oct 24;21(49):7524-32 12386815 Cancer Res. 2002 Nov 15;62(22):6456-61 12438235 Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15524-9 12434020 Nat Rev Cancer. 2002 Dec;2(12):897-909 12459728 Mol Cell Biol. 2003 Jan;23(1):206-15 12482974 Immunology. 2003 Jan;108(1):32-41 12519300 Nat Rev Cancer. 2004 Jan;4(1):45-60 14681689 Nature. 1992 Dec 3;360(6403):458-61 1448168 Cancer. 1993 Apr 1;71(7):2191-9 8384065 Hum Pathol. 1997 Mar;28(3):344-52 9042800 Pathol Int. 1997 Dec;47(12):813-30 9503463 Cancer Res. 1998 Sep 15;58(18):4079-81 9751614 Cancer Res. 1999 Aug 15;59(16):4083-9 10463611 Biochem J. 2004 Dec 1;384(Pt 2):263-70 15260802 J Mol Med (Berl). 2005 Feb;83(2):97-109 15592805 N Engl J Med. 2005 Oct 27;353(17):1793-801 16251535 Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15785-90 16243968 J Biol Chem. 2006 Aug 18;281(33):23676-85 16737958 Int J Cancer. 2006 Oct 15;119(8):1850-7 16721789 Gastroenterology. 2006 Nov;131(5):1501-17 17101324 J Mol Med (Berl). 2006 Dec;84(12):1055-66 17058067 Cancer Res. 2008 Apr 15;68(8):2708-16 18413738 PLoS One. 2008;3(4):e2054 18446242 N Engl J Med. 2008 May 1;358(18):1919-28 18450603 Proteomics. 2008 Aug;8(16):3329-41 18651706 Nature. 2008 Sep 4;455(7209):64-71 18668037 Mucosal Immunol. 2008 May;1(3):183-97 19079178 Nature. 2009 Jan 22;457(7228):396-404 19158785 Br J Cancer. 2009 Jan 27;100(2):344-51 19127263 Cell Cycle. 2009 Feb 1;8(3):377-82 19177007 Cancer Sci. 2010 Jan;101(1):259-66 19817750 J Hepatobiliary Pancreat Sci. 2010 Mar;17(2):108-24 19787286 Biochem Biophys Res Commun. 2010 Jun 25;397(2):333-9 20510874 Gastroenterology. 2002 Oct;123(4):1052-60 12360467 3' Untranslated Regions Carcinoma, Pancreatic Ductal diagnosis genetics metabolism pathology Cell Line, Tumor DNA Methylation DNA, Neoplasm genetics metabolism Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Histone Deacetylases metabolism Histones genetics metabolism Humans Male MicroRNAs metabolism Mucins diagnostic use genetics metabolism Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic RNA Processing, Post-Transcriptional RNA, Messenger genetics metabolism Tumor Markers, Biological PMC3010767 2010 10 6 2010 10 8 6 0 2010 10 12 6 0 2011 6 2 6 0 ppublish cwq155 10.1093/glycob/cwq155 20926598 PMC3010767 20924086 2010 12 01 2011 01 06

1460-2180 31 12 2010 Dec Carcinogenesis Methylation-associated silencing of microRNA-34b/c in gastric cancer and its involvement in an epigenetic field defect. 2066-73 10.1093/carcin/bgq203 Altered expression of microRNA (miRNA) is strongly implicated in cancer, and recent studies have shown that the silencing of some miRNAs is associated with CpG island hypermethylation. To identify epigenetically silenced miRNAs in gastric cancer (GC), we screened for miRNAs induced by treatment with 5-aza-2'-deoxycytidine and 4-phenylbutyrate. We found that miR-34b and miR-34c are epigenetically silenced in GC and that their downregulation is associated with hypermethylation of the neighboring CpG island. Methylation of the miR-34b/c CpG island was frequently observed in GC cell lines (13/13, 100%) but not in normal gastric mucosa from Helicobacter pylori-negative healthy individuals. Transfection of a precursor of miR-34b and miR-34c into GC cells induced growth suppression and dramatically changed the gene expression profile. Methylation of miR-34b/c was found in a majority of primary GC specimens (83/118, 70%). Notably, analysis of non-cancerous gastric mucosae from GC patients (n = 109) and healthy individuals (n = 85) revealed that methylation levels are higher in gastric mucosae from patients with multiple GC than in mucosae from patients with single GC (27.3 versus 20.8%; P < 0.001) or mucosae from H. pylori-positive healthy individuals (27.3 versus 20.7%; P < 0.001). These results suggest that miR-34b and miR-34c are novel tumor suppressors frequently silenced by DNA methylation in GC, that methylation of miR-34b/c is involved in an epigenetic field defect and that the methylation might be a predictive marker of GC risk. Suzuki Hiromu H First Department of Internal Medicine, Sapporo Medical University, S1, W16, Chuo-Ku, Sapporo 064-8543, Japan. Yamamoto Eiichiro E Nojima Masanori M Kai Masahiro M Yamano Hiro-O HO Yoshikawa Kenjiro K Kimura Tomoaki T Kudo Toyoki T Harada Eiji E Sugai Tamotsu T Takamaru Hiroyuki H Niinuma Takeshi T Maruyama Reo R Yamamoto Hiroyuki H Tokino Takashi T Imai Kohzoh K Toyota Minoru M Shinomura Yasuhisa Y eng Journal Article Research Support, Non-U.S. Gov't 2010 10 05

England Carcinogenesis 8008055 0143-3334 0 MIRN34 microRNA, human 0 MicroRNAs IM Cell Line, Tumor DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Gene Silencing Humans MicroRNAs analysis antagonists & inhibitors physiology Oligonucleotide Array Sequence Analysis Stomach Neoplasms genetics 2010 10 5 2010 10 7 6 0 2010 10 7 6 0 2011 1 7 6 0 ppublish bgq203 10.1093/carcin/bgq203 20924086 20848182 2011 03 16 2011 07 15

1573-7217 126 3 2011 Apr Breast Cancer Res. Treat. Let-7a regulation of insulin-like growth factors in breast cancer. 687-94 10.1007/s10549-010-1168-5 Expression of certain microRNA genes is regulated by DNA methylation, which in turn affects the activities of their downstream molecules. Our previous study showed that methylated let-7a-3 was associated with low IGF-II expression and favorable prognosis of ovarian cancer. The roles of let-7a-3 methylation in breast cancer and in regulation of IGF expression in the tumor are still unknown. Let-7a-3 methylation, IGF mRNAs, and peptides were analyzed in 348 breast cancer samples using quantitative methylation-specific PCR, qRT-PCR, and ELISA, respectively. The associations of let-7a-3 methylation with IGFs, disease features, and patient survivals were analyzed. In vitro experiments were performed using HeLa cells transfected with let-7a precursors to assess the effect of let-7a on IGF expression. Let-7a-3 methylation was detected frequently in breast cancer. An inverse correlation between let-7a-3 methylation and IGF expression was observed in breast cancer, which was similar to that seen in ovarian cancer. Our in vitro experiment showed that let-7a could increase IGF expression in cancer cells which had low endogenous let-7a. Let-7a-3 methylation was also found to be associated with high grade tumors and ER- or PR-negative cancer. However, let-7a-3 methylation was not associated with disease-free survival or overall survival of breast cancer patients. The study provides further evidence in support of the notion that epigenetic regulation of let-7a-3 may affect the actions of IGFs in cancer. Let-7a may up-regulate the expression of IGFs in cancer cells, which is different from its inhibitory effects on other oncogenes. Lu Lingeng L Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034, USA. Katsaros Dionyssios D Zhu Yong Y Hoffman Aaron A Luca Scarampi S Marion Canuto Emilie CE Mu Lina L Risch Harvey H Yu Herbert H eng Journal Article 2010 09 17

Netherlands Breast Cancer Res Treat 8111104 0167-6806 0 MicroRNAs 0 Somatomedins 0 mirnlet7 microRNA, human IM Adult Aged Aged, 80 and over Breast Neoplasms metabolism DNA Methylation Enzyme-Linked Immunosorbent Assay methods Gene Expression Regulation, Neoplastic HeLa Cells Humans MicroRNAs metabolism physiology Middle Aged Prognosis Reverse Transcriptase Polymerase Chain Reaction methods Somatomedins metabolism 2010 7 28 2010 9 4 2010 9 17 2010 9 18 6 0 2010 9 18 6 0 2011 7 16 6 0 ppublish 10.1007/s10549-010-1168-5 20848182 20847817 2010 9 17

1661-3791 5 2 2010 Breast Care (Basel) Epigenetic Signatures in Breast Cancer: Clinical Perspective. 66-73 There is now a compelling body of evidences sustaining the importance of epigenetic mechanisms in the development and progression of cancer. DNA methylation, post-translational histone and other protein modifications, microRNA expression, and nucleosome positioning, all act together to exert their cellular effects. The epigenome is responsible for controlling gene expression thus defining cell differentiation and tissue specificity. This review will focus on DNA methylation and histone modification because these epigenetic events are widely implicated in cancer development and progression. We will in particular address the translational aspects of breast cancer epigenomics including the development of biomarkers and the prospects for epigenetic based pharmacologic treatments. The analysis of DNA methylation has the advantage over other molecular methods (e.g. single gene mutation, microsatellite analysis) that it can be detected with a very high degree of specificity even in the presence of excess unmethylated DNA. Furthermore, the presence of specific CpG methylation signatures makes methylation-based markers attractive diagnostic, prognostic, and predictive tools for better management of breast cancer patients. Parrella Paola P Laboratorio di Oncologia, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. ENG JOURNAL ARTICLE 2010 4 23

Breast Care (Basel) 101254060 1661-3791 2010 4 23 2010 9 18 6 0 2010 9 18 6 0 2010 9 18 6 0 ppublish 10.1159/000309138 20847817 PMC2931038 309138 20841926 2010 09 15 2010 10 19

0385-0684 37 9 2010 Sep Gan To Kagaku Ryoho [Molecular mechanisms involved in epigenetic alterations in cancer]. 1650-3 Epigenetic alterations such as DNA methylation and histone modification play a role in gene silencing in tumorigenesis. DNA methylation affects the expression of genes involved in cell cycle checkpoint, apoptosis, and DNA repair. Recently, epigenetic alterations are shown to play a role in silencing microRNA. Mutations of DNA methyltransferase and histone modification enzymes such as DNMT3A, UTX and EZH2 have been shown in various types of tumors. Genes involved in epigenetic regulation may be novel targets of cancer therapy in the near future. Toyota Minoru M Dept. of Biochemistry, Sapporo Medical University, Chuo-ku, Sapporo, Japan. Suzuki Hiromu H Nishizaka Takahiro T Sato Akiko A Yamashita Toshiharu T jpn English Abstract Journal Article

Japan Gan To Kagaku Ryoho 7810034 0385-0684 0 MicroRNAs IM DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics Mutation Neoplasms drug therapy genetics metabolism 2010 9 16 6 0 2010 9 16 6 0 2010 10 20 6 0 ppublish 20841926 20841507 2010 12 17 2011 02 08 2013 11 21

1528-0020 116 25 2010 Dec 16 Blood BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. 5660-9 10.1182/blood-2010-06-290536 BAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene-embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients. Schwind Sebastian S Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. Marcucci Guido G Maharry Kati K Radmacher Michael D MD Mrózek Krzysztof K Holland Kelsi B KB Margeson Dean D Becker Heiko H Whitman Susan P SP Wu Yue-Zhong YZ Metzeler Klaus H KH Powell Bayard L BL Kolitz Jonathan E JE Carter Thomas H TH Moore Joseph O JO Baer Maria R MR Carroll Andrew J AJ Caligiuri Michael A MA Larson Richard A RA Bloomfield Clara D CD eng CA101140 CA NCI NIH HHS United States CA114725 CA NCI NIH HHS United States CA129657 CA NCI NIH HHS United States CA140158 CA NCI NIH HHS United States CA16058 CA NCI NIH HHS United States CA31946 CA NCI NIH HHS United States CA33601 CA NCI NIH HHS United States CA77658 CA NCI NIH HHS United States P50 CA140158 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010 09 14

United States Blood 7603509 0006-4971 0 BAALC protein, human 0 ERG protein, human 0 MicroRNAs 0 Neoplasm Proteins 0 RNA, Messenger 0 Trans-Activators 0 Tumor Markers, Biological 04079A1RDZ Cytarabine ZS7284E0ZP Daunorubicin AIM IM Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13814-9 19666492 J Clin Oncol. 2010 May 10;28(14):2348-55 20368543 Blood. 2001 Mar 1;97(5):1172-9 11222358 Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13901-6 11707601 Blood. 2002 Mar 15;99(6):2037-44 11877277 Genes Chromosomes Cancer. 2002 Jun;34(2):137-53 11979548 Blood. 2002 Jun 15;99(12):4326-35 12036858 J Biol Chem. 2002 Jul 12;277(28):25026-31 11978794 Blood. 2003 Sep 1;102(5):1613-8 12750167 J Clin Oncol. 2004 Feb 15;22(4):624-33 14726504 Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3915-20 15007164 Cancer Res. 1994 Jun 1;54(11):2865-8 8187069 Cancer Res. 1996 Mar 15;56(6):1418-25 8640834 Blood. 1997 May 1;89(9):3323-9 9129038 Eur J Haematol. 1997 Mar;58(3):137-53 9150707 Clin Cancer Res. 2005 Feb 15;11(4):1416-24 15746041 Leuk Lymphoma. 2005 Jun;46(6):885-91 16019534 Stem Cells. 2005 Sep;23(8):1142-53 16140871 Cancer Cell. 2005 Nov;8(5):355-68 16286244 Blood. 2005 Dec 1;106(12):3740-6 16051734 Proc Natl Acad Sci U S A. 2005 Dec 13;102(50):18081-6 16330772 J Clin Oncol. 2005 Dec 20;23(36):9234-42 16275934 Cancer Sci. 2006 Feb;97(2):113-8 16441421 PLoS Genet. 2005 Sep;1(3):e28 16151515 J Clin Oncol. 2006 Feb 10;24(5):790-7 16418499 Blood. 2006 Jul 1;108(1):63-73 16522815 Blood. 2006 Nov 15;108(10):3280-8 16840728 J Clin Invest. 2007 Jan;117(1):206-17 17160136 Blood. 2007 Jan 15;109(2):431-48 16960150 Leukemia. 2007 Mar;21(3):566-8 17252007 J Clin Oncol. 2007 May 10;25(14):1908-15 17488990 Oncogene. 2007 Jun 14;26(28):4148-57 17260024 J Clin Oncol. 2007 Aug 1;25(22):3337-43 17577018 Oncogene. 2007 Oct 15;26(47):6766-76 17934484 RNA. 2008 May;14(5):872-7 18367714 N Engl J Med. 2008 May 1;358(18):1919-28 18450603 Blood. 2008 Jun 1;111(11):5371-9 18378853 Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9053-8 18574145 Int J Oncol. 2008 Aug;33(2):239-44 18636143 J Clin Oncol. 2008 Nov 1;26(31):5078-87 18809607 Cell Cycle. 2009 Feb 1;8(3):394-8 19176999 J Clin Oncol. 2009 Jul 1;27(19):3198-204 19451432 Carcinogenesis. 2009 Jul;30(7):1139-46 19423649 Blood. 2010 Jan 21;115(3):453-74 19880497 J Clin Oncol. 2010 Feb 1;28(4):596-604 20026798 Blood. 2010 Aug 5;116(5):788-92 20442368 Ann Hematol. 2010 May;89(5):453-8 19943049 Int J Lab Hematol. 2010 Apr;32(2):197-205 19555438 J Clin Oncol. 2009 Oct 20;27(30):5031-8 19752345 Aged Aged, 80 and over Antineoplastic Combined Chemotherapy Protocols therapeutic use Cytarabine administration & dosage Cytogenetic Analysis Daunorubicin administration & dosage Female Gene Expression Profiling Humans Leukemia, Myeloid, Acute drug therapy genetics pathology Male MicroRNAs genetics Middle Aged Neoplasm Proteins genetics Oligonucleotide Array Sequence Analysis RNA, Messenger genetics Reverse Transcriptase Polymerase Chain Reaction Survival Rate Trans-Activators genetics Treatment Outcome Tumor Markers, Biological genetics PMC3031412 2010 9 14 2010 9 16 6 0 2010 9 16 6 0 2011 2 9 6 0 ppublish blood-2010-06-290536 10.1182/blood-2010-06-290536 20841507 PMC3031412 20841484 2010 10 15 2010 11 23 2014 01 16

1538-7445 70 20 2010 Oct 15 Cancer Res. MicroRNA mediates DNA demethylation events triggered by retinoic acid during neuroblastoma cell differentiation. 7874-81 10.1158/0008-5472.CAN-10-1534 Neuroblastoma is an often fatal pediatric cancer arising from precursor cells of the sympathetic nervous system. 13-Cis retinoic acid is included in the treatment regimen for patients with high-risk disease, and a similar derivative, all-trans-retinoic acid (ATRA), causes neuroblastoma cell lines to undergo differentiation. The molecular signaling pathways involved with ATRA-induced differentiation are complex, and the role that DNA methylation changes might play are unknown. The purpose of this study was to evaluate the genome-wide effects of ATRA on DNA methylation using methylated DNA immunoprecipitation applied to microarrays representing all known promoter and CpG islands. Four hundred and two gene promoters became demethylated, whereas 88 were hypermethylated post-ATRA. mRNA expression microarrays revealed that 82 of the demethylated genes were overexpressed by >2-fold, whereas 13 of the hypermethylated genes were underexpressed. Gene ontology analysis indicated that demethylated and re-expressed genes were enriched for signal transduction pathways, including NOS1, which is required for neural cell differentiation. As a potential mechanism for the DNA methylation changes, we show the downregulation of methyltransferases, DNMT1 and DNMT3B, along with the upregulation of endogenous microRNAs targeting them. Ectopic overexpression of miR-152, targeting DNMT1, also negatively affected cell invasiveness and anchorage-independent growth, contributing in part to the differentiated phenotype. We conclude that functionally important, miRNA-mediated DNA demethylation changes contribute to the process of ATRA-induced differentiation resulting in the activation of NOS1, a critical determinant of neural cell differentiation. Our findings illustrate the plasticity and dynamic nature of the epigenome during cancer cell differentiation. Das Sudipto S Department of Cancer Genetics, Royal College of Surgeons, Ireland. Foley Niamh N Bryan Kenneth K Watters Karen M KM Bray Isabella I Murphy Derek M DM Buckley Patrick G PG Stallings Raymond L RL eng R01 CA127496-01A1 CA NCI NIH HHS United States R01 CA127496-02 CA NCI NIH HHS United States R01 CA127496-03 CA NCI NIH HHS United States R01 CA127496-04 CA NCI NIH HHS United States Journal Article Research Support, Non-U.S. Gov't 2010 09 14

United States Cancer Res 2984705R 0008-5472 0 MicroRNAs 5688UTC01R Tretinoin EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 EC 2.1.1.37 DNA methyltransferase 3A EC 2.1.1.37 DNA methyltransferase 3B IM J Nutr. 2002 Mar;132(3):365-9 11880556 Nat Genet. 2003 Jan;33(1):61-5 12496760 Bioinformatics. 2003 Jan 22;19(2):185-93 12538238 Nat Rev Cancer. 2003 Mar;3(3):203-16 12612655 Cancer Res. 2003 Aug 1;63(15):4538-46 12907629 Biostatistics. 2003 Apr;4(2):249-64 12925520 J Cell Sci. 2004 Sep 15;117(Pt 20):4727-37 15331636 Science. 1984 Jun 8;224(4653):1121-4 6719137 Cell Differ. 1984 Jun;14(2):135-44 6467378 Nature. 1985 Jan 31-Feb 6;313(6001):404-6 3855502 N Engl J Med. 1985 Oct 31;313(18):1111-6 4047115 Exp Cell Biol. 1988;56(6):321-33 3066661 Oncogene. 1996 Aug 15;13(4):803-12 8761302 J Neurooncol. 1997 Jan;31(1-2):65-83 9049832 J Pharmacol Exp Ther. 2004 Dec;311(3):968-81 15302897 Bioinformatics. 2005 Nov 1;21(21):4067-8 16141249 Cancer Res. 2007 Feb 1;67(3):976-83 17283129 Proc Natl Acad Sci U S A. 2007 May 8;104(19):7957-62 17483472 Int J Oncol. 2008 Mar;32(3):625-31 18292940 Cancer Res. 2008 Dec 1;68(23):9654-62 19047142 J Cell Biochem. 2009 May 1;107(1):46-57 19277986 Mol Cell Biol. 2009 Oct;29(19):5290-305 19635812 PLoS One. 2009;4(11):e7850 19924232 FASEB J. 2009 Dec;23(12):4276-87 19713529 PLoS One. 2009;4(12):e8154 19997598 Genome Biol. 2008;9(10):R150 18851746 Oncogene. 2010 Mar 4;29(9):1394-404 19946337 Hepatology. 2010 Mar;51(3):881-90 20146264 Cell Differentiation drug effects Cell Division Colony-Forming Units Assay DNA (Cytosine-5-)-Methyltransferase genetics DNA Methylation genetics Gene Expression Profiling Genes, Reporter Humans MicroRNAs genetics Neoplasm Invasiveness Neuroblastoma pathology Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Reverse Transcriptase Polymerase Chain Reaction Transfection Tretinoin pharmacology NIHMS234691 PMC2955783 2010 9 14 2010 10 5 2010 9 16 6 0 2010 9 16 6 0 2010 12 14 6 0 ppublish 0008-5472.CAN-10-1534 10.1158/0008-5472.CAN-10-1534 20841484 PMC2955783 NIHMS234691 20822491 2010 09 08 2010 12 23

1744-1358 48 1 2010 Sep 20 Essays Biochem. Epigenetic regulation of cell life and death decisions and deregulation in cancer. 121-46 10.1042/bse0480121 For every cell, there is a time to live and a time to die. It is apparent that cell life and death decisions are taken by individual cells based on their interpretation of physiological or non-physiological stimuli, or their own self-assessment of internal damage or changes in their environment. Apoptosis or programmed cell death is a key regulator of physiological growth control and regulation of tissue homoeostasis. One of the most important advances in cancer research in recent years is the recognition that cell death, mostly by apoptosis, is crucially involved in the regulation of tumour formation and also critically determines treatment response. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modifications and microRNA expression, has revealed a plethora of events that contribute to the neoplastic phenotype through stable changes in the expression of genes critical to cell death pathways. A better understanding of the epigenetic molecular events that regulate apoptosis, together with the reversible nature of epigenetic aberrations, should contribute to the emergence of the promising field of epigenetic therapy. Hajji Nabil N Department of Experimental Medicine and Toxicology, Division of Investigative Science, Imperial College, London, UK. n.hajji@imperial.ac.uk Joseph Bertrand B eng Journal Article Research Support, Non-U.S. Gov't Review

England Essays Biochem 0043306 0071-1365 IM Animals Apoptosis genetics Cell Line, Tumor DNA Methylation Epigenesis, Genetic Humans 2010 9 9 6 0 2010 9 9 6 0 2010 12 25 6 0 ppublish bse0480121 10.1042/bse0480121 20822491 20682481 2011 01 04 2011 03 22 2013 11 21

1552-9924 119 1 2011 Jan Environ. Health Perspect. An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis. 11-9 10.1289/ehp.1002114 Exposure to arsenic, an established human carcinogen, through consumption of highly contaminated drinking water is a worldwide public health concern. Several mechanisms by which arsenical compounds induce tumorigenesis have been proposed, including oxidative stress, genotoxic damage, and chromosomal abnormalities. Recent studies have suggested that epigenetic mechanisms may also mediate toxicity and carcinogenicity resulting from arsenic exposure. We examined the evidence supporting the roles of the three major epigenetic mechanisms-DNA methylation, histone modification, and microRNA (miRNA) expression-in arsenic toxicity and, in particular, carcinogenicity. We also investigated future research directions necessary to clarify epigenetic and other mechanisms in humans. We conducted a PubMed search of arsenic exposure and epigenetic modification through April 2010 and summarized the in vitro and in vivo research findings, from both our group and others, on arsenic-associated epigenetic alteration and its potential role in toxicity and carcinogenicity. Arsenic exposure has been shown to alter methylation levels of both global DNA and gene promoters; histone acetylation, methylation, and phosphorylation; and miRNA expression, in studies analyzing mainly a limited number of epigenetic end points. Systematic epigenomic studies in human populations exposed to arsenic or in patients with arsenic-associated cancer have not yet been performed. Such studies would help to elucidate the relationship between arsenic exposure, epigenetic dysregulation, and carcinogenesis and are becoming feasible because of recent technological advancements. Ren Xuefeng X Division of Environmental Health Sciences, School of Public Health, University of California–Berkeley, Berkeley, California 94720, USA. xfr@berkeley.edu McHale Cliona M CM Skibola Christine F CF Smith Allan H AH Smith Martyn T MT Zhang Luoping L eng P42 ES004705 ES NIEHS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Review 2010 08 02

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metabolism Oxidative Stress PMC3018488 2010 3 02 2010 8 02 2010 8 02 2010 8 5 6 0 2010 8 5 6 0 2011 3 23 6 0 ppublish 10.1289/ehp.1002114 20682481 PMC3018488 20651980 2010 07 23 2010 11 05 2013 10 23

1476-5586 12 7 2010 Jul Neoplasia Tumor-initiating and -propagating cells: cells that we would like to identify and control. 506-15 Identification of the cell types capable of initiating and sustaining growth of the neoplastic clone in vivo is a fundamental problem in cancer research. It is likely that tumor growth can be sustained both by rare cancer stem-like cells and selected aggressive clones and that the nature of the mutations, the cell of origin, and its environment will contribute to tumor propagation. Genomic instability, suggested as a driving force in tumorigenesis, may be induced by genetic and epigenetic changes. The feature of self-renewal in stem cells is shared with tumor cells, and deviant function of the stem cell regulatory networks may, in complex ways, contribute to malignant transformation and the establishment of a cancer stem cell-like phenotype. Understanding the nature of the more quiescent cancer stem-like cells and their niches has the potential to develop novel cancer therapeutic protocols including pharmacological targeting of self-renewal pathways. Drugs that target cancer-related inflammation may have the potential to reeducate a tumor-promoting microenvironment. Because most epigenetic modifications may be reversible, DNA methylation and histone deacetylase inhibitors can be used to induce reexpression of genes that have been silenced epigenetically. Design of therapies that eliminate cancer stem-like cells without eliminating normal stem cells will be important. Further insight into the mechanisms by which pluripotency transcription factors (e.g., OCT4, SOX2, and Nanog), polycomb repressive complexes and microRNA balance selfrenewal and differentiation will be essential for our understanding of both embryonic differentiation and human carcinogenesis and for the development of new treatment strategies. Tysnes Berit Bølge BB NorLux Neuro Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway. berit.tysnes@biomed.uib.no eng Journal Article Research Support, Non-U.S. Gov't Review

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discussion 1895-6 16488983 Cancer Res. 2006 May 1;66(9):4553-7 16651403 Nature. 2006 May 25;441(7092):475-82 16598206 Nature. 2006 May 25;441(7092):518-22 16633340 Eur J Cancer. 2006 Jun;42(9):1213-8 16632344 Nat Genet. 2006 Jul;38(7):738-40 16804535 Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4147-53 16857785 Nat Rev Cancer. 2006 Nov;6(11):846-56 17060944 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 J Cell Physiol. 2007 Feb;210(2):279-89 17096367 Nature. 2006 Dec 7;444(7120):756-60 17051156 Nature. 2006 Dec 7;444(7120):761-5 17151667 Oncogene. 2006 Dec 14;25(59):7663-72 16847453 Nature. 2007 Jan 4;445(7123):111-5 17122771 Nature. 2007 Jan 4;445(7123):106-10 17122772 Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8 17210912 Nat Genet. 2007 Feb;39(2):157-8 17200673 Cancer Res. 2007 Feb 1;67(3):1030-7 17283135 Cell. 2007 Feb 23;128(4):683-92 17320506 Semin Cancer Biol. 2007 Jun;17(3):191-203 16762563 Cancer Res. 2007 May 1;67(9):4010-5 17483311 Gastroenterology. 2007 Jun;132(7):2542-56 17570225 Cell Differentiation physiology Cell Proliferation Cell Separation methods Cell Transformation, Neoplastic pathology Humans Infection complications pathology Inflammation complications pathology Models, Biological Neoplasm Invasiveness pathology Neoplasms pathology Neoplastic Stem Cells pathology Regeneration physiology PMC2907577 2010 2 17 2010 3 26 2010 3 29 2010 7 24 6 0 2010 7 24 6 0 2010 11 6 6 0 ppublish 20651980 PMC2907577 20610616 2010 10 19 2011 02 22

1460-2407 16 11 2010 Nov Mol. Hum. Reprod. MicroRNA signature in testes-derived male germ-line stem cells. 804-10 10.1093/molehr/gaq058 The testis-derived male germ-line stem (GS) cell, the in vitro counterpart of spermatogonial stem cell (SSC), can initiate donor-derived spermatogenesis in recipient testes and therefore, has been viewed as a future therapeutic modality for treatment of male infertility in azoospermic patients and in cancer patients who are expecting chemotherapy. Upon extended in vitro culture, GS cells also generate a second cell type called multipotent adult germ-line stem (maGS) cell which, upon testicular transplantation, produces teratoma instead of initiating spermatogenesis. Here, we show that expressions of both Let-7a and Let-7d were consistently higher while that of miR-294 (embryonic stem cell-cycle-regulating miRNA; ESCC) was lower in GS cells than in maGS cells. Furthermore, among several putative targets of Let-7 identified by in silico bioinformatics, expressions of Igf2 and H19 mRNA targets significantly differed between GS and maGS cells. However, although the CTCF binding factor (a component of DNA methylation machinery at Igf2-H19 cluster) was also a putative target for Let-7, the difference in expressions of Igf2 and H19 between GS and maGS cells was not mediated through a change in DNA methylation. Both GS and maGS cells maintained androgenetic imprinting at the Igf2-H19 imprinting control region and Peg1 differentially methylated region. In conclusion, our study suggests that high Let-7 expression may be a unique property of GS cells and expressions of Let-7 and ESCC miRNAs may serve as miRNA signatures to distinguish them from maGS cells during clinical transplantation, to avoid the likelihood of teratoma formation due to maGS cells generated during extended in vitro culture of GS cells. Jung Yoon Hee YH Department of Bioscience and Biotechnology, Konkuk University, 1, Hwayang-dong, Gwangjin-gu, Seoul 143 701, South Korea. Gupta Mukesh Kumar MK Shin Ji Young JY Uhm Sang Jun SJ Lee Hoon Taek HT eng Journal Article Research Support, Non-U.S. Gov't 2010 07 07

England Mol Hum Reprod 9513710 1360-9947 0 MicroRNAs 0 RNA, Messenger 0 mirnlet7 microRNA, mouse IM Adult Stem Cells cytology Animals Computer Simulation Gene Expression Regulation Germ Cells metabolism Male Mice MicroRNAs genetics Multipotent Stem Cells cytology RNA, Messenger metabolism Testis cytology 2010 7 7 2010 7 9 6 0 2010 7 9 6 0 2011 2 23 6 0 ppublish gaq058 10.1093/molehr/gaq058 20610616 20588276 2010 07 14 2010 08 05 2013 11 21

1532-1827 103 2 2010 Jul 13 Br. J. Cancer The functional significance of microRNA-145 in prostate cancer. 256-64 10.1038/sj.bjc.6605742 MicroRNAs (miRNAs) are small noncoding RNAs that have important roles in numerous cellular processes. Recent studies have shown aberrant expression of miRNAs in prostate cancer tissues and cell lines. On the basis of miRNA microarray data, we found that miR-145 is significantly downregulated in prostate cancer. We investigated the expression and functional significance of miR-145 in prostate cancer. The expression of miR-145 was low in all the prostate cell lines tested (PC3, LNCaP and DU145) compared with the normal cell line, PWR-1E, and in cancerous regions of human prostate tissue when compared with the matched adjacent normal. Overexpression of miR-145 in PC3-transfected cells resulted in increased apoptosis and an increase in cells in the G2/M phase, as detected by flow cytometry. Investigation of the mechanisms of inactivation of miR-145 through epigenetic pathways revealed significant DNA methylation of the miR-145 promoter region in prostate cancer cell lines. Microarray analyses of miR-145-overexpressing PC3 cells showed upregulation of the pro-apoptotic gene TNFSF10, which was confirmed by real-time PCR and western analysis. One of the genes significantly upregulated by miR-145 overexpression is the proapoptotic gene TNFSF10. Therefore, modulation of miR-145 may be an important therapeutic approach for the management of prostate cancer. Zaman M S MS Department of Urology, San Francisco Veterans Affairs Medical Center and University of California at San Francisco, San Francisco, CA, USA. Chen Y Y Deng G G Shahryari V V Suh S O SO Saini S S Majid S S Liu J J Khatri G G Tanaka Y Y Dahiya R R eng R01CA111470 CA NCI NIH HHS United States R01CA138642 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2010 06 29

England Br J Cancer 0370635 0007-0920 0 Hydroxamic Acids 0 MIRN145 microRNA, human 0 MicroRNAs 0 TNF-Related Apoptosis-Inducing Ligand 0 TNFSF10 protein, human 3X2S926L3Z trichostatin A 776B62CQ27 decitabine DH2M523P0H Genistein M801H13NRU Azacitidine IM Cancer Res. 2004 May 1;64(9):2988-93 15126330 CA Cancer J Clin. 2004 May-Jun;54(3):150-80 15195789 Nat Rev Genet. 2004 Jul;5(7):522-31 15211354 Cell. 1987 Sep 11;50(6):823-9 3113737 Cell. 1990 Apr 20;61(2):203-12 2158859 J Biol Chem. 1996 May 31;271(22):12687-90 8663110 Nutr Cancer. 1997;27(1):31-40 8970179 Cancer Res. 1998 Jan 1;58(1):95-101 9426064 J Immunol. 1998 Sep 15;161(6):2833-40 9743343 J Natl Cancer Inst. 1998 Nov 4;90(21):1637-47 9811313 Cancer Res. 1998 Dec 1;58(23):5315-20 9850056 Nat Med. 1999 Feb;5(2):157-63 9930862 Nat Genet. 1999 Feb;21(2):163-7 9988266 Cancer Causes Control. 1998 Dec;9(6):553-7 10189040 Nature. 2005 Feb 17;433(7027):769-73 15685193 Cell Death Differ. 2005 May;12(5):482-91 15746940 Cancer Res. 2005 Aug 15;65(16):7065-70 16103053 Clin Prostate Cancer. 2005 Sep;4(2):124-9 16197614 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Cancer Cell. 2006 Mar;9(3):189-98 16530703 CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66 17237035 Int J Cancer. 2007 Mar 1;120(5):1046-54 17149698 JAMA. 2007 May 2;297(17):1901-8 17473300 J Immunol. 2002 Feb 1;168(3):1356-61 11801676 Nat Rev Cancer. 2001 Dec;1(3):194-202 11902574 Nat Rev Cancer. 2002 Jul;2(7):537-43 12094240 J Nutr. 2002 Aug;132(8 Suppl):2419S-2423S 12163704 Bioinformatics. 2002 Nov;18(11):1427-31 12424112 Science. 2003 Jul 18;301(5631):336-8 12869753 Br J Nutr. 2004 Apr;91(4):513-31 15035679 Cancer Res. 2007 Jul 1;67(13):6092-9 17616664 Cancer Res. 2007 Jul 1;67(13):6130-5 17616669 J Biol Chem. 2007 Aug 10;282(32):23716-24 17569667 Cancer Res. 2007 Sep 1;67(17):7972-6 17804704 Oncologist. 2007 Oct;12(10):1247-52 17962618 Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19983-8 18056640 Int J Cancer. 2008 Mar 1;122(5):969-77 18098138 Cancer Res. 2008 Jan 15;68(2):425-33 18199536 JAMA. 2008 Jan 30;299(4):425-36 18230780 Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1608-13 18227514 Cancer Sci. 2008 Feb;99(2):280-6 18201269 Cancer Cell. 2008 Mar;13(3):272-86 18328430 Oncogene. 2008 Mar 13;27(12):1788-93 17891175 Cancer Res. 2008 Apr 15;68(8):2745-54 18417445 Cell Mol Life Sci. 2008 Jul;65(13):2105-17 18535780 Cancer Res. 2008 Aug 1;68(15):6416-24 18676867 Nature. 2008 Sep 4;455(7209):64-71 18668037 J Cell Mol Med. 2008 Dec;12(6A):2457-66 18266964 PLoS One. 2009;4(4):e5130 19340314 Cell Death Differ. 2010 Feb;17(2):246-54 19730444 Br J Cancer. 2011 Mar 1;104(5):892 Apoptosis Azacitidine analogs & derivatives pharmacology Cell Cycle Cell Line, Tumor DNA Methylation Down-Regulation Gene Silencing Genistein pharmacology Humans Hydroxamic Acids pharmacology Male MicroRNAs physiology Microarray Analysis Prostatic Neoplasms genetics TNF-Related Apoptosis-Inducing Ligand genetics Up-Regulation PMC2906737 2010 6 29 2010 7 1 6 0 2010 7 1 6 0 2010 8 6 6 0 ppublish 6605742 10.1038/sj.bjc.6605742 20588276 PMC2906737 20551052 2010 07 02 2010 08 09 2014 09 22

1538-7445 70 13 2010 Jul 1 Cancer Res. Pancreatic cancers epigenetically silence SIP1 and hypomethylate and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels. 5226-37 10.1158/0008-5472.CAN-09-4227 Aberrant DNA methylation and microRNA expression play important roles in the pathogenesis of pancreatic cancer. While interrogating differentially methylated CpG islands in pancreatic cancer, we identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer. We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition. In a panel of 23 pancreatic cell lines, we observed a reciprocal correlation between miR-200, SIP1, and E-cadherin expression, with pancreatic cancer-associated fibroblasts showing the opposite expression pattern to most pancreatic cancers. In Panc-1 cells, which express SIP1, have low E-cadherin expression, and do not express miR-200a or miR-200b, treatment with miR-200a and miR-200b downregulated SIP1 mRNA and increased E-cadherin expression. However, most pancreatic cancers express miR-200a and miR-200b, but this expression does not affect SIP1 expression, as the SIP1 promoter is silenced by hypermethylation and in these cancers E-cadherin is generally expressed. Both miR-200a and miR-200b were significantly elevated in the sera of pancreatic cancer and chronic pancreatitis patients compared with healthy controls (P < 0.0001), yielding receiver operating characteristic curve areas of 0.861 and 0.85, respectively. In conclusion, most pancreatic cancers display hypomethylation and overexpression of miR-200a and miR-200b, silencing of SIP1 by promoter methylation, and retention of E-cadherin expression. The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility. Copyright 2010 AACR. Li Ang A Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21231, USA. Omura Noriyuki N Hong Seung-Mo SM Vincent Audrey A Walter Kimberly K Griffith Margaret M Borges Michael M Goggins Michael M eng CA120432 CA NCI NIH HHS United States CA62924 CA NCI NIH HHS United States P50 CA062924 CA NCI NIH HHS United States P50 CA062924-130008 CA NCI NIH HHS United States R01 CA120432 CA NCI NIH HHS United States R01 CA120432-05 CA NCI NIH HHS United States RC2 CA148346 CA NCI NIH HHS United States RC2 CA148346-01 CA NCI NIH HHS United States RC2CA148346 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010 06 15

United States Cancer Res 2984705R 0008-5472 0 Cadherins 0 GEMIN2 protein, human 0 MIRN200 microRNA, human 0 MicroRNAs 0 Nerve Tissue Proteins 0 RNA-Binding Proteins IM BMC Mol Biol. 2008;9:76 18718003 EMBO Rep. 2008 Jun;9(6):582-9 18483486 Cancer Res. 2008 Oct 1;68(19):7846-54 18829540 Clin Gastroenterol Hepatol. 2008 Nov;6(11):1270-8 18995218 Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3536-42 19064568 Expert Rev Gastroenterol Hepatol. 2007 Oct;1(1):81-8 19072437 Cancer Res. 2009 Mar 15;69(6):2400-7 19276344 Science. 2009 Apr 10;324(5924):217 19264984 Am J Pathol. 2009 May;174(5):1588-93 19342369 Gastrointest Endosc. 2009 May;69(6):1095-102 19152896 Gastroenterology. 2009 Jul;137(1):361-71, 371.e1-5 19362090 CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49 19474385 Cancer Res. 2009 Jul 15;69(14):5820-8 19584296 Cancer Res. 2009 Aug 15;69(16):6704-12 19654291 Clin Cancer Res. 2009 Aug 15;15(16):5060-72 19671845 Cancer Res. 2009 Sep 1;69(17):6765-8; discussion 6769 19706773 Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2380-5 19723916 Cancer Prev Res (Phila). 2009 Sep;2(9):807-13 19723895 Gut. 2009 Oct;58(10):1375-81 19201770 Nat Rev Genet. 2009 Oct;10(10):704-14 19763153 J Biol Chem. 2008 May 30;283(22):14910-4 18411277 Br J Haematol. 2008 May;141(5):672-5 18318758 Cancer Biol Ther. 2008 Mar;7(3):353-360 18075308 Proc Natl Acad Sci U S A. 2008 Jul 29;105(30):10513-8 18663219 Cancer Biol Ther. 2008 Jul;7(7):1146-56 18535405 Gastroenterology. 2010 Mar;138(3):1166-77 20026066 Clin Cancer Res. 2010 Mar 15;16(6):1781-9 20215540 Cancer Res. 2000 Apr 1;60(7):1835-9 10766168 EMBO J. 2003 May 15;22(10):2453-62 12743039 Cancer Res. 2003 Jul 1;63(13):3735-42 12839967 Cancer Res. 2003 Jul 15;63(14):4158-66 12874021 Cancer. 2005 Apr 15;103(8):1631-43 15742334 Clin Cancer Res. 2005 Jul 1;11(13):4681-8 16000561 Cancer Res. 2006 Jan 15;66(2):1208-17 16424060 Gastroenterology. 2006 Feb;130(2):548-65 16472607 Cancer Cell. 2006 Jun;9(6):435-43 16766263 Clin Gastroenterol Hepatol. 2006 Jun;4(6):766-81; quiz 665 16682259 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 J Clin Oncol. 2007 Jan 20;25(3):319-25 17235047 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Oncogene. 2007 Apr 5;26(16):2381-5 17043655 Cell Cycle. 2007 May 2;6(9):1001-5 17457051 Clin Cancer Res. 2008 Jan 15;14(2):412-8 18223216 Genes Dev. 2008 Apr 1;22(7):894-907 18381893 Clin Cancer Res. 2008 May 1;14(9):2690-5 18451233 Nat Cell Biol. 2008 May;10(5):593-601 18376396 Science. 2008 Sep 26;321(5897):1801-6 18772397 Adult Cadherins biosynthesis genetics Carcinoma, Pancreatic Ductal blood genetics metabolism Case-Control Studies Cell Line, Tumor DNA Methylation Female Gene Silencing Humans Male MicroRNAs biosynthesis blood genetics Middle Aged Nerve Tissue Proteins biosynthesis genetics Pancreatic Neoplasms blood genetics metabolism RNA-Binding Proteins biosynthesis genetics NIHMS206694 PMC3130565 2010 6 15 2010 6 17 6 0 2010 6 17 6 0 2010 8 10 6 0 ppublish 0008-5472.CAN-09-4227 10.1158/0008-5472.CAN-09-4227 20551052 PMC3130565 NIHMS206694 20540697 2010 06 16 2010 10 07

1875-5453 11 5 2010 Jun 1 Curr. Drug Metab. Epigenetic remedies by dietary phytochemicals against inflammatory skin disorders: myth or reality? 436-50 While many botanicals have been used during thousands of years in various cultures for the treatment of several inflammatory conditions, wound healing or preserving skin beauty, their active ingredients and their mechanisms of action are less well characterized. It is known that throughout life, environmental conditions and dietary compounds influence gene expression. Only recently it has been observed that exposure to specific phytochemicals can affect gene expression via reversible epigenetic mechanisms and gets recorded in our "epigenome" through life. Epigenetics refers to heritable phenotypical differences or changes in gene expression that are not attributable to changes in DNA sequence, but rather depend on variations in DNA methylation, chromatin structure or microRNA profiles. As such, our dietary epigenetic imprint superposed on our genome may rewire gene expression patterns in the body and the host immune system, and protect against inflammatory disorders, cancer and ageing. This has recently launched reexploration of nutritional, botanical or phytopharmaceutical compounds for epigenetic effects to identify promising nutraceuticals or cosmeceuticals which could (re)program stem cell differentiation, wound healing, skin regeneration, tissue homeostasis, or "correct" epigenetic marks responsible for inflammatory skin disorders and ageing. Vanden Berghe Wim W Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Department of Physiology, Ghent University, K.L. Ledeganckstraat 35, Gent, Belgium. wim.vandenberghe@ua.ac.be Haegeman Guy G eng Journal Article Research Support, Non-U.S. Gov't Review

Netherlands Curr Drug Metab 100960533 1389-2002 0 Anti-Inflammatory Agents, Non-Steroidal IM Animals Anti-Inflammatory Agents, Non-Steroidal pharmacology therapeutic use Dermatitis drug therapy metabolism physiopathology prevention & control Drug Discovery Epigenesis, Genetic drug effects Gene Expression Regulation drug effects Humans Phytotherapy 362 2010 4 5 2010 5 17 2010 6 15 6 0 2010 6 15 6 0 2010 10 12 6 0 ppublish BSP/CDM/E-Pub/00074 20540697 20495621 2012 01 06 2012 04 16 2014 09 22

1750-192X 1 2 2009 Dec Epigenomics Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment. 387-98 10.2217/epi.09.25 We have previously shown that the microenvironment of human embryonic stem cells (hESCs) is able to change and reprogram aggressive cancer cells to a less aggressive state. Some mechanisms implicated in the phenotypic changes observed after this exposure are mainly associated with the Nodal signaling pathway, which plays a key role in tumor cell plasticity. However, several other molecular mechanisms might be related directly and/or indirectly to these changes, including microRNA (miRNA) regulation and DNA methylation. To further explore the epigenetic mechanisms potentially underlying the phenotypic changes that occur after exposing metastatic melanoma cells to a hESC microenvironment. A total of 365 miRNAs were screened using the TaqMan® Low Density Arrays. We also evaluated whether DNA methylation could be one of the factors regulating the expression of the inhibitor of Nodal, Lefty, in hESCs (where it is highly expressed) vs melanoma cells (where it is not expressed). Using these experimental approaches, we identified miRNAs that are up- and down-regulated in melanoma cells exposed to a hESC microenvironment, such as miR-302a and miR-27b, respectively. We also demonstrate that Notch4 is one of the targets of miR-302a, which is upstream of Nodal. Additionally, one of the mechanisms that might explain the absence of the inhibitor of Nodal, Lefty, in cancer cells is silencing by DNA methylation, which provides new insights into the unregulated expression of Nodal in melanoma. These findings suggest that epigenetic changes such as DNA methylation and regulation by microRNAs might play a significant role in tumor cell plasticity and the metastatic phenotype. Costa Fabricio F FF Cancer Biology and Epigenomics Program, Children’s Memorial Research Center and Northwestern University’s Feinberg School of Medicine, 2300 Children’s Plaza, Chicago, IL 60614, USA. mjchendrix@childrensmemorial.org Seftor Elisabeth A EA Bischof Jared M JM Kirschmann Dawn A DA Strizzi Luigi L Arndt Kelly K Bonaldo Maria de Fatima Mde F Soares Marcelo B MB Hendrix Mary J C MJ eng CA121205 CA NCI NIH HHS United States CA59702 CA NCI NIH HHS United States R01 CA121205 CA NCI NIH HHS United States R01 CA121205-03 CA NCI NIH HHS United States R37 CA059702 CA NCI NIH HHS United States R37 CA059702-17 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

England Epigenomics 101519720 1750-192X 0 LEFTY1 protein, human 0 Left-Right Determination Factors 0 MIRN27 microRNA, human 0 MIRN302 microRNA, human 0 MicroRNAs 0 NODAL protein, human 0 Nodal Protein EC 1.13.12.- Luciferases IM Genes Dev. 2003 May 15;17(10):1207-12 12730124 J Clin Oncol. 2001 Aug 15;19(16):3622-34 11504744 Mamm Genome. 2008 Aug;19(7-8):526-40 18636290 Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16608-13 18931301 Mol Cell Biol. 2008 Oct;28(20):6426-38 18710938 RNA. 2008 Oct;14(10):2115-24 18755840 Cell. 2008 Aug 8;134(3):521-33 18692474 Nat Biotechnol. 2008 Apr;26(4):462-9 18362881 Cancer Treat Rev. 2007 Dec;33(8):665-80 17919823 Nature. 2007 Oct 11;449(7163):682-8 17898713 Pharmacogenomics J. 2007 Oct;7(5):297-304 17189960 Circ Res. 2007 Jul 6;101(1):59-68 17540974 Nature. 2007 Jun 28;447(7148):1130-4 17554337 J Cell Biochem. 2007 Jul 1;101(4):908-17 17177292 Nat Rev Cancer. 2007 Apr;7(4):246-55 17384580 Expert Opin Ther Targets. 2007 Apr;11(4):497-505 17373879 Cell. 2007 Feb 23;128(4):683-92 17320506 Annu Rev Cell Dev Biol. 2003;19:589-621 14570583 Nucleic Acids Res. 1988 Nov 25;16(22):10881-90 2849754 Cell. 2009 Jun 12;137(6):1032-46 19524507 Dev Cell. 2009 Apr;16(4):517-27 19386261 J Invest Dermatol. 2009 May;129(5):1219-24 19005486 Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1814-9 19188590 Cell. 2009 Jan 23;136(2):215-33 19167326 Gene. 2007 Jan 15;386(1-2):1-10 17113247 Nature. 2008 Jan 10;451(7175):147-52 18185580 Trends Mol Med. 2006 Dec;12(12):580-7 17071139 Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4329-34 18334633 Adv Exp Med Biol. 2008;624:89-103 18348450 Nat Med. 2006 Aug;12(8):925-32 16892036 Stem Cells. 2006 Mar;24(3):501-5 16293574 Cancer Genet Cytogenet. 2006 Mar;165(2):135-43 16527607 Cell. 2005 Jul 15;122(1):6-7 16009126 Semin Cell Dev Biol. 1998 Dec;9(6):599-607 9918871 Genome Res. 1998 Mar;8(3):186-94 9521922 Nucleic Acids Res. 1997 Sep 1;25(17):3389-402 9254694 Int J Cancer. 1991 Jan 21;47(2):227-37 1671030 Blotting, Western Cell Culture Techniques Cell Line, Tumor Computational Biology CpG Islands genetics DNA Methylation physiology Embryonic Stem Cells metabolism Epigenesis, Genetic genetics physiology Gene Expression Profiling Gene Expression Regulation, Neoplastic genetics physiology Humans Left-Right Determination Factors metabolism Luciferases Melanoma genetics physiopathology MicroRNAs metabolism Models, Biological Neoplasm Metastasis genetics physiopathology Nodal Protein metabolism Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA methods DNA methylation Lefty Nodal Notch hESC microenvironment microRNAs 2010 5 25 6 0 2010 5 25 6 0 2012 4 17 6 0 ppublish 10.2217/epi.09.25 20495621 PMC2872497 NIHMS171922 20493980 2010 12 07 2011 02 09

0006-3002 1799 10-12 2010 Oct-Dec Biochim. Biophys. Acta Interplay between microRNAs and the epigenetic machinery: an intricate network. 694-701 10.1016/j.bbagrm.2010.05.005 microRNAs take their place into the epigenetic world revealing a complicated network of reciprocal interconnections: not only they are able to control gene expression at a post-transcriptional level, thus representing a new important class of regulatory molecules, but they are also directly connected to the epigenetic machinery through a regulatory loop. Indeed, if epigenetic modifications, such as DNA methylation or histone acetylation, have been demonstrated to affect microRNA expression, and to be potentially responsible for the aberrant miRNA regulation observed in cancer, the other side of the coin is represented by the capacity of microRNAs to control the epigenetic machinery directly targeting its enzymatic components. This review will analyze and describe the regulatory loop interconnecting microRNAs and epigenetics, describing either how epigenetics can affect the miRNome, as well as how epi-miRNAs can control the epigenome, particularly focusing on the alterations observed in human cancer. Copyright © 2010 Elsevier B.V. All rights reserved. Iorio Marilena V MV Molecular Targeting Unit, Experimental Oncology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. Piovan Claudia C Croce Carlo M CM eng Journal Article Research Support, Non-U.S. Gov't Review 2010 05 20

Netherlands Biochim Biophys Acta 0217513 0006-3002 0 Histones 0 MicroRNAs IM Acetylation Animals DNA Methylation genetics Epigenesis, Genetic Histones genetics metabolism Humans Methylation MicroRNAs genetics metabolism Neoplasms genetics metabolism 2010 3 8 2010 5 8 2010 5 20 2010 5 25 6 0 2010 5 25 6 0 2011 2 10 6 0 ppublish S1874-9399(10)00066-0 10.1016/j.bbagrm.2010.05.005 20493980 20478395 2011 06 02 2011 08 23

0027-5107 722 2 2011 Jun 17 Mutat. Res. Sex-specific radiation-induced microRNAome responses in the hippocampus, cerebellum and frontal cortex in a mouse model. 114-8 10.1016/j.mrgentox.2010.05.007 Ionizing radiation is an important treatment modality, but it is also a well-known genotoxic agent capable of damaging cells and tissues. Therefore radiation treatment can cause numerous side effects in exposed tissues and organs. Radiotherapy is a part of the front-line treatment regime for brain cancer patients, but can cause severe functional and morphological changes in exposed brain tissues. However, the mechanisms of radiation-induced effects in the brain are not well understood and are under-investigated. Recent data has implicated short RNAs, especially microRNAs, as important in radiation responses, yet nothing is known about radiation-induced changes in the brain microRNAome. We analyzed the effects of X-ray irradiation on microRNA expression in the hippocampus, frontal cortex, and cerebellum of male and female mice. Here, we report tissue-, time-, and sex-specific brain radiation responses, as well as show evidence of an interplay between microRNAs and their targets. Specifically, we show that changes in the expression of the miR-29 family may be linked, at least in part, to altered expression of de novo methyltransferase DNMT3a and changed global DNA methylation levels. Further, these sex-specific epigenetic changes may be correlated to the prevalence of radiation-induced cancers in males. We identified several microRNAs that can potentially serve as biomarkers of brain radiation exposure. In summary, our study may provide an important roadmap for further analysis of microRNA expression in different brain regions of male and female mice and for detailed dissection of radiation-induced brain responses. Copyright © 2010 Elsevier B.V. All rights reserved. Koturbash Igor I Department of Biological Sciences, University of Lethbridge, Lethbridge, AB, Canada. Zemp Franz F Kolb Bryan B Kovalchuk Olga O eng Canadian Institutes of Health Research Canada Journal Article Research Support, Non-U.S. Gov't 2010 05 15

Netherlands Mutat Res 0400763 0027-5107 0 MicroRNAs IM Animals Cerebellum metabolism radiation effects DNA Damage DNA Methylation Female Frontal Lobe metabolism radiation effects Hippocampus metabolism radiation effects Male Mice Mice, Inbred C57BL MicroRNAs radiation effects Organ Specificity Sex Characteristics X-Rays 2010 4 28 2010 5 8 2010 5 15 2010 5 19 6 0 2010 5 19 6 0 2011 8 24 6 0 ppublish S1383-5718(10)00173-7 10.1016/j.mrgentox.2010.05.007 20478395 20467450 2010 07 19 2010 10 22

1476-5500 17 8 2010 Aug Cancer Gene Ther. MicroRNA and drug resistance. 523-31 10.1038/cgt.2010.18 Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA) dysregulation. miRNAs are endogenously expressed small non-coding RNAs, which are evolutionarily conserved and function as regulators of gene expression. Much effort has been exerted in analyzing the role of miRNAs in the development of drug resistance in a variety of malignancies. Several research groups have shown that the expressions of miRNAs in chemoresistant cancer cells and their parental chemosensitive ones are different. The molecular targets and mechanisms of chemosensitivity and chemoresistance are also elucidated. This article reviews the functions of miRNAs in the development of drug resistance. Ma J J Department of Hematology, Qilu Hospital, Shandong University, Jinan, Shandong, China. Dong C C Ji C C eng Journal Article Review 2010 05 14

England Cancer Gene Ther 9432230 0929-1903 0 MicroRNAs IM Drug Resistance, Neoplasm genetics Humans MicroRNAs biosynthesis genetics Neoplasms drug therapy genetics 2010 5 14 2010 5 15 6 0 2010 5 15 6 0 2010 10 23 6 0 ppublish cgt201018 10.1038/cgt.2010.18 20467450 20431052 2010 06 29 2010 07 08

1530-8561 56 7 2010 Jul Clin. Chem. The silencing of microRNA 148a production by DNA hypermethylation is an early event in pancreatic carcinogenesis. 1107-18 10.1373/clinchem.2010.144709 The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is accounted for by the absence of early diagnostic markers and effective treatments. MicroRNAs inhibit the translation of their target mRNAs. The production of microRNAs is strongly altered in cancers, but the causes of these alterations are only partially known. DNA hypermethylation is a major cause of gene inactivation in cancer. Our aims were to identify microRNAs whose gene expression is inactivated by hypermethylation in PDAC and to determine whether this hypermethylation-mediated repression is an early event during pancreatic carcinogenesis. We also sought to investigate whether these differentially methylated regions can serve as a diagnostic marker for PDAC. MicroRNA production was measured by microarray hybridization and reverse-transcription quantitative PCR. The level of DNA methylation was measured by bisulfite mapping and semiquantitative methylation-specific PCR. We identified 29 microRNAs encoded by genes whose expression is potentially inactivated by DNA hypermethylation. We focused our study on microRNA 148a (miR-148a) and found its production to be repressed, not only in PDAC samples but also in preneoplastic pancreatic intraepithelial neoplasia (PanIN) lesions. More importantly, we found that hypermethylation of the DNA region encoding miR-148a is responsible for its repression, which occurs in PanIN preneoplastic lesions. Finally, we show that the hypermethylated DNA region encoding miR-148a can serve as an ancillary marker for the differential diagnosis of PDAC and chronic pancreatitis (CP). We show that the hypermethylation of the DNA region encoding miR-148a is responsible for its repression in PDAC precursor lesions and can be a useful tool for the differential diagnosis of PDAC and CP. Hanoun Naïma N INSERM, U858, Toulouse, France. Delpu Yannick Y Suriawinata Arief A AA Bournet Barbara B Bureau Christophe C Selves Janick J Tsongalis Gregory J GJ Dufresne Marlène M Buscail Louis L Cordelier Pierre P Torrisani Jérôme J eng Journal Article Research Support, Non-U.S. Gov't 2010 04 29

United States Clin Chem 9421549 0009-9147 0 MIRN148 microRNA, human 0 MicroRNAs IM Animals Carcinoma, Pancreatic Ductal diagnosis metabolism pathology Cell Line, Tumor DNA Methylation Diagnosis, Differential Down-Regulation Gene Silencing Humans Mice Mice, Mutant Strains MicroRNAs biosynthesis genetics Pancreatic Neoplasms diagnosis metabolism pathology Pancreatitis, Chronic diagnosis Polymerase Chain Reaction Precancerous Conditions diagnosis metabolism pathology 2010 4 29 2010 5 1 6 0 2010 5 1 6 0 2010 7 9 6 0 ppublish clinchem.2010.144709 10.1373/clinchem.2010.144709 20431052 20404328 2010 06 15 2010 07 21 2014 04 17

1083-351X 285 25 2010 Jun 18 J. Biol. Chem. Microarray-based transcriptional and epigenetic profiling of matrix metalloproteinases, collagens, and related genes in cancer. 19647-59 10.1074/jbc.M109.088153 Epigenetic parameters (DNA methylation, histone modifications, and miRNAs) play a significant role in cancer. To identify the common epigenetic signatures of both the individual matrix metalloproteinases (MMPs) and the additional genes, the function of which is also linked to proteolysis, migration, and tumorigenesis, we performed epigenetic profiling of 486 selected genes in unrelated non-migratory MCF-7 breast carcinoma and highly migratory U251 glioma cells. Genome-wide transcriptional profiling, quantitative reverse transcription-PCR, and microRNA analyses were used to support the results of our epigenetic studies. Transcriptional silencing in both glioma and breast carcinoma cells predominantly involved the repressive histone H3 Lys-27 trimethylation (H3K27me3) mark. In turn, epigenetic stimulation was primarily performed through a gain in the histone H3 Lys-4 dimethylation (H3K4me2) and H3 hyperacetylation and by a global reduction of H3K27me3. Inactive pro-invasive genes in MCF-7 cells but not in U251 cells frequently exhibited a stem cell-like bivalent mark (enrichment in both H3K27me3 and H3K4me2), a characteristic of developmental genes. In contrast with other MMPs, MMP-8 was epigenetically silenced in both cell types, thus providing evidence for the strict epigenetic control of this anti-tumorigenic proteinase in cancer. Epigenetic stimulation of multiple collagen genes observed in cultured glioma cells was then directly confirmed using orthotopic xenografts and tumor specimens. We suggest that the epigenetic mechanisms allow gliomas to deposit an invasion-promoting collagen-enriched matrix and then to use this matrix to accomplish their rapid migration through the brain tissue. Chernov Andrei V AV Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA. Baranovskaya Svetlana S Golubkov Vladislav S VS Wakeman Dustin R DR Snyder Evan Y EY Williams Roy R Strongin Alex Y AY eng GEO GSE18899 CA77470 CA NCI NIH HHS United States CA83017 CA NCI NIH HHS United States P30 CA030199 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2010 04 19

United States J Biol Chem 2985121R 0021-9258 EC 3.4.24.- Matrix Metalloproteinases IM Nat Rev Genet. 2009 Oct;10(10):704-14 19763153 Hum Mol Genet. 2009 Oct 1;18(19):3594-604 19584087 Expert Rev Anticancer Ther. 2009 Nov;9(11):1663-74 19895249 J Cell Sci. 2009 Nov 15;122(Pt 22):4042-8 19861500 Brain Res. 2010 Feb 2;1312:120-6 19948152 Lab Invest. 2010 Feb;90(2):144-55 20048743 Int J Oncol. 2010 Apr;36(4):913-20 20198336 PLoS One. 2010;5(3):e9808 20339555 Science. 2008 Sep 26;321(5897):1807-12 18772396 Methods Mol Biol. 2000;132:365-86 10547847 J Biol Chem. 2000 Dec 15;275(50):39237-45 11007770 Nature. 2001 Mar 1;410(6824):116-20 11242053 Nature. 2001 Mar 1;410(6824):120-4 11242054 Curr Biol. 2001 Mar 6;11(5):R185-97 11267889 Science. 2001 Apr 6;292(5514):110-3 11283354 J Biol Chem. 2001 Mar 9;276(10):6983-92 11114293 Genes Dev. 2001 Sep 15;15(18):2343-60 11562345 Nat Genet. 2002 Jan;30(1):77-80 11740497 Genomics. 1992 Jul;13(3):881-3 1639418 Biol Chem. 1997 Mar-Apr;378(3-4):151-60 9165065 Nat Struct Mol Biol. 2005 Feb;12(2):110-2 15702071 Curr Opin Struct Biol. 2005 Feb;15(1):107-15 15718141 Arthritis Rheum. 2005 Oct;52(10):3110-24 16200590 Cancer Cell. 2006 Apr;9(4):287-300 16616334 Cell. 2006 Apr 21;125(2):315-26 16630819 Nat Genet. 2006 May;38(5):500-1 16642009 Nat Cell Biol. 2006 May;8(5):532-8 16570078 J Biol Chem. 2006 Sep 8;281(36):26196-204 16849317 IUBMB Life. 2006 Oct;58(10):589-96 17050376 Proc Natl Acad Sci U S A. 2006 Oct 24;103(43):15782-7 17043231 Front Biosci. 2007;12:528-35 17127314 Clin Cancer Res. 2006 Dec 1;12(23):7009-17 17145822 Cell. 2007 Feb 23;128(4):693-705 17320507 Oncogene. 2007 Apr 19;26(18):2563-73 17099729 Cell. 2007 May 18;129(4):823-37 17512414 Oncogene. 2007 Aug 9;26(36):5229-37 17325663 Cell. 2007 Oct 5;131(1):29-32 17923085 J Immunol. 2008 Apr 1;180(7):5036-44 18354229 Cell Stem Cell. 2007 Sep 13;1(3):286-98 18371363 Cancer Res. 2008 Apr 15;68(8):2755-63 18413742 Nat Genet. 2008 May;40(5):499-507 18443585 Cancer Metastasis Rev. 2008 Jun;27(2):289-302 18286233 J Biol Chem. 2008 May 30;283(22):14910-4 18411277 BMC Med. 2008;6:14 18577219 Cancer Res. 2008 Sep 15;68(18):7247-9 18794108 Cancer Res. 2002 Jan 15;62(2):580-8 11809713 Nat Rev Cancer. 2002 Mar;2(3):161-74 11990853 Nat Rev Genet. 2002 Jun;3(6):415-28 12042769 Biochem Biophys Res Commun. 2002 Oct 4;297(4):765-72 12359218 Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66 12360192 Circ Res. 2003 May 2;92(8):827-39 12730128 Cell. 2004 Jan 23;116(2):281-97 14744438 J Cell Physiol. 2004 Jul;200(1):11-9 15137053 Cancer Lett. 2008 Dec 18;272(2):197-205 19013014 Nat Genet. 2009 May;41(5):518-20 19330028 J Biol Chem. 2009 May 8;284(19):12727-34 19286653 Int J Oncol. 2009 Jun;34(6):1653-60 19424584 Biochem Biophys Res Commun. 2009 Aug 14;386(1):1-5 19523920 Annu Rev Med. 2009;60:167-79 19630570 Invest Ophthalmol Vis Sci. 2009 Aug;50(8):3542-52 19387070 J Biol Chem. 2009 Oct 23;284(43):29893-904 19625257 Animals Cell Line, Tumor DNA Methylation Dimerization Epigenesis, Genetic Female Gene Expression Profiling Gene Expression Regulation, Enzymologic Humans Matrix Metalloproteinases metabolism Mice Mice, Inbred BALB C Mice, SCID Neoplasm Transplantation Neoplasms metabolism Oligonucleotide Array Sequence Analysis PMC2885243 2010 4 19 2010 4 21 6 0 2010 4 21 6 0 2010 7 22 6 0 ppublish M109.088153 10.1074/jbc.M109.088153 20404328 PMC2885243 20197299 2010 05 06 2010 05 14 2014 05 20

1460-2180 31 5 2010 May Carcinogenesis MicroRNA-137 promoter methylation in oral rinses from patients with squamous cell carcinoma of the head and neck is associated with gender and body mass index. 864-70 10.1093/carcin/bgq051 Head and neck cancer represents 3.3% of all new malignancies and 2.0% of cancer deaths in the USA, the majority of which are squamous in origin. The overall 5 year survival is 60% and worsens with increasing stage at diagnosis. Thus, novel biomarkers for early detection of squamous cell carcinoma of the head and neck (SCCHN) are needed. MicroRNA-137 (miR-137) plays a role in cell cycle control and seems to undergo promoter methylation in oral squamous cell carcinoma tissue. The main objectives of this study were to ascertain whether miR-137 promoter methylation is detectable in oral rinse samples, assess its association with SCCHN and identify potential risk factors for its occurrence. Oral rinse samples were collected from 99 SCCHN patients with no prior history of cancer and 99 cancer-free controls, frequency matched on gender; tumor tissue for 64 patients was also tested. Methylation of the miR-137 promoter, assessed using methylation-specific polymerase chain reaction, was detected in 21.2% oral rinses from SCCHN patients and 3.0% from controls [odds ratio (OR) = 4.80, 95% confidence interval (CI): 1.23-18.82]. Among cases, promoter methylation of miR-137 was associated with female gender (OR = 5.30, 95% CI: 1.20-23.44) and inversely associated with body mass index (BMI) (OR = 0.88, 95% CI: 0.77-0.99). Promoter methylation of miR-137 appears to be a relatively frequently detected event in oral rinse of SCCHN patients and may have future utility as a biomarker in DNA methylation panels. The observed associations with gender and BMI help to shed light on potential risk factors for an altered methylation state in SCCHN. Langevin Scott M SM Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA. Stone Roslyn A RA Bunker Clareann H CH Grandis Jennifer R JR Sobol Robert W RW Taioli Emanuela E eng 5TL1RR024155-03 RR NCRR NIH HHS United States P50 CA097190 CA NCI NIH HHS United States P50CA097190-01A1 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010 03 02

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1573-7233 29 1 2010 Mar Cancer Metastasis Rev. Integrating the multiple dimensions of genomic and epigenomic landscapes of cancer. 73-93 10.1007/s10555-010-9199-2 Advances in high-throughput, genome-wide profiling technologies have allowed for an unprecedented view of the cancer genome landscape. Specifically, high-density microarrays and sequencing-based strategies have been widely utilized to identify genetic (such as gene dosage, allelic status, and mutations in gene sequence) and epigenetic (such as DNA methylation, histone modification, and microRNA) aberrations in cancer. Although the application of these profiling technologies in unidimensional analyses has been instrumental in cancer gene discovery, genes affected by low-frequency events are often overlooked. The integrative approach of analyzing parallel dimensions has enabled the identification of (a) genes that are often disrupted by multiple mechanisms but at low frequencies by any one mechanism and (b) pathways that are often disrupted at multiple components but at low frequencies at individual components. These benefits of using an integrative approach illustrate the concept that the whole is greater than the sum of its parts. As efforts have now turned toward parallel and integrative multidimensional approaches for studying the cancer genome landscape in hopes of obtaining a more insightful understanding of the key genes and pathways driving cancer cells, this review describes key findings disseminating from such high-throughput, integrative analyses, including contributions to our understanding of causative genetic events in cancer cell biology. Chari Raj R Genetics Unit - Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada. rchari@bccrc.ca Thu Kelsie L KL Wilson Ian M IM Lockwood William W WW Lonergan Kim M KM Coe Bradley P BP Malloff Chad A CA Gazdar Adi F AF Lam Stephen S Garnis Cathie C MacAulay Calum E CE Alvarez Carlos E CE Lam Wan L WL eng 5U01 CA84971-10 CA NCI NIH HHS United States HG004663 HG NHGRI NIH HHS United States MOP 77903 Canadian Institutes of Health Research Canada MOP 86731 Canadian Institutes of Health Research Canada P50 CA070907-090003 CA NCI NIH HHS United States P50 CA070907-100003 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

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1097-0215 127 8 2010 Oct 15 Int. J. Cancer Alterations of microRNAs and their targets are associated with acquired resistance of MCF-7 breast cancer cells to cisplatin. 1785-94 10.1002/ijc.25191 Cancer cells that develop resistance to chemotherapeutic agents are a major clinical obstacle in the successful treatment of breast cancer. Acquired cancer chemoresistance is a multifactorial phenomenon, involving various mechanisms and processes. Recent studies suggest that chemoresistance may be linked to drug-induced dysregulation of microRNA function. Furthermore, mounting evidence indicates the existence of similarities between drug-resistant and metastatic cancer cells in terms of resistance to apoptosis and enhanced invasiveness. We studied the role of miRNA alterations in the acquisition of cisplatin-resistant phenotype in MCF-7 human breast adenocarcinoma cells. We identified a total of 103 miRNAs that were overexpressed or underexpressed (46 upregulated and 57 downregulated) in MCF-7 cells resistant to cisplatin. These differentially expressed miRNAs are involved in the control of cell signaling, cell survival, DNA methylation and invasiveness. The most significantly dysregulated miRNAs were miR-146a, miR-10a, miR-221/222, miR-345, miR-200b and miR-200c. Furthermore, we demonstrated that miR-345 and miR-7 target the human multidrug resistance-associated protein 1. These results suggest that dysregulated miRNA expression may underlie the abnormal functioning of critical cellular processes associated with the cisplatin-resistant phenotype. Pogribny Igor P IP Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA. igor.pogribny@fda.hhs.gov Filkowski Jody N JN Tryndyak Volodymyr P VP Golubov Andrey A Shpyleva Svitlana I SI Kovalchuk Olga O eng Journal Article Research Support, Non-U.S. Gov't

United States Int J Cancer 0042124 0020-7136 0 Antineoplastic Agents 0 MicroRNAs 0 Multidrug Resistance-Associated Proteins 0 RNA, Messenger 0 Tumor Markers, Biological 0 multidrug resistance-associated protein 1 EC 1.13.12.- Luciferases Q20Q21Q62J Cisplatin IM Antineoplastic Agents pharmacology Blotting, Western Breast Neoplasms drug therapy genetics pathology Cisplatin pharmacology Drug Resistance, Neoplasm Female Gene Expression Profiling Humans Luciferases metabolism MicroRNAs physiology Multidrug Resistance-Associated Proteins genetics metabolism Oligonucleotide Array Sequence Analysis RNA, Messenger genetics Reverse Transcriptase Polymerase Chain Reaction Tumor Cells, Cultured Tumor Markers, Biological genetics metabolism 2010 1 26 6 0 2010 1 26 6 0 2010 9 24 6 0 ppublish 10.1002/ijc.25191 20099276 20084174 2010 01 19 2010 05 20 2014 09 11

1932-6203 5 1 2010 PLoS ONE Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. e8697 10.1371/journal.pone.0008697 The microRNA-200 family participates in the maintenance of an epithelial phenotype and loss of its expression can result in epithelial to mesenchymal transition (EMT). Furthermore, the loss of expression of miR-200 family members is linked to an aggressive cancer phenotype. Regulation of the miR-200 family expression in normal and cancer cells is not fully understood. Epigenetic mechanisms participate in the control of miR-200c and miR-141 expression in both normal and cancer cells. A CpG island near the predicted mir-200c/mir-141 transcription start site shows a striking correlation between miR-200c and miR-141 expression and DNA methylation in both normal and cancer cells, as determined by MassARRAY technology. The CpG island is unmethylated in human miR-200/miR-141 expressing epithelial cells and in miR-200c/miR-141 positive tumor cells. The CpG island is heavily methylated in human miR-200c/miR-141 negative fibroblasts and miR-200c/miR-141 negative tumor cells. Mouse cells show a similar inverse correlation between DNA methylation and miR-200c expression. Enrichment of permissive histone modifications, H3 acetylation and H3K4 trimethylation, is seen in normal miR-200c/miR-141-positive epithelial cells, as determined by chromatin immunoprecipitation coupled to real-time PCR. In contrast, repressive H3K9 dimethylation marks are present in normal miR-200c/miR-141-negative fibroblasts and miR-200c/miR-141 negative cancer cells and the permissive histone modifications are absent. The epigenetic modifier drug, 5-aza-2'-deoxycytidine, reactivates miR-200c/miR-141 expression showing that epigenetic mechanisms play a functional role in their transcriptional control. We report that DNA methylation plays a role in the normal cell type-specific expression of miR-200c and miR-141 and this role appears evolutionarily conserved, since similar results were obtained in mouse. Aberrant DNA methylation of the miR-200c/141 CpG island is closely linked to their inappropriate silencing in cancer cells. Since the miR-200c cluster plays a significant role in EMT, our results suggest an important role for DNA methylation in the control of phenotypic conversions in normal cells. Vrba Lukas L Arizona Cancer Center, The University of Arizona, Tucson, Arizona, USA. Jensen Taylor J TJ Garbe James C JC Heimark Ronald L RL Cress Anne E AE Dickinson Sally S Stampfer Martha R MR Futscher Bernard W BW eng K07 CA132956 CA NCI NIH HHS United States P30CA023074 CA NCI NIH HHS United States P30ES06694 ES NIEHS NIH HHS United States R01 CA065662 CA NCI NIH HHS United States R01 CA065662-10A2 CA NCI NIH HHS United States R01CA65662 CA NCI NIH HHS United States U54 CA112970 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. 2010 01 13

United States PLoS One 101285081 1932-6203 0 Histones 0 MIRN141 microRNA, human 0 MIRN200 microRNA, human 0 MicroRNAs IM Nature. 2002 Dec 5;420(6915):520-62 12466850 Int J Cancer. 2000 Mar 15;85(6):805-10 10709100 J Virol. 1969 Nov;4(5):549-53 4311790 Proc Natl Acad Sci U S A. 1977 Sep;74(9):3918-21 302945 Int J Cancer. 1978 Mar 15;21(3):274-81 631930 Invest Urol. 1979 Jul;17(1):16-23 447482 Cancer Res. 1983 Apr;43(4):1809-18 6831420 J Mol Biol. 1987 Jul 20;196(2):261-82 3656447 Am J Pathol. 1999 Sep;155(3):787-98 10487836 J Cell Biol. 1963 May;17:299-313 13985244 Nature. 2005 Jun 9;435(7043):834-8 15944708 Neoplasia. 2005 Sep;7(9):799-808 16229802 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 BMC Bioinformatics. 2006;7:446 17038168 Oncogene. 2007 Jan 4;26(1):77-90 16799634 J Cell Physiol. 2007 Nov;213(2):374-83 17680632 Cancer Res. 2007 Sep 1;67(17):7972-6 17804704 Cancer Res. 2007 Sep 15;67(18):8699-707 17875710 Nature. 2007 Oct 11;449(7163):682-8 17898713 Genes Dev. 2008 Apr 1;22(7):894-907 18381893 Clin Cancer Res. 2008 May 1;14(9):2690-5 18451233 Nat Cell Biol. 2008 May;10(5):593-601 18376396 BMC Mol Biol. 2008;9:34 18400113 EMBO Rep. 2008 Jun;9(6):582-9 18483486 Carcinogenesis. 1999 Nov;20(11):2063-73 10545407 Mamm Genome. 2009 Sep-Oct;20(9-10):674-80 19777308 Nat Genet. 2000 Sep;26(1):61-3 10973249 Nat Genet. 2002 Jun;31(2):175-9 12021783 Hepatology. 2008 Jun;47(6):1955-63 18433021 Clin Exp Metastasis. 2008;25(6):629-42 18461285 Carcinogenesis. 2008 Aug;29(8):1500-8 18448484 BMC Genomics. 2008;9:486 18922183 Science. 2008 Dec 12;322(5908):1695-9 19008416 Nat Rev Mol Cell Biol. 2009 Feb;10(2):126-39 19165215 Cell Cycle. 2009 Mar 15;8(6):843-52 19221491 Cancer Res. 2009 Mar 15;69(6):2623-9 19258506 Am J Pathol. 2009 Apr;174(4):1131-8 19264914 Curr Opin Cell Biol. 2009 Jun;21(3):470-9 19411171 J Gastroenterol. 2009;44(6):556-61 19363643 Cancer Res. 2009 Jun 15;69(12):5251-8 19509227 Cell Mol Life Sci. 2009 May;66(10):1682-99 19153653 Cell. 2009 Aug 7;138(3):592-603 19665978 Stem Cells. 2009 Aug;27(8):1712-21 19544444 Cancer Res. 2009 Oct 1;69(19):7557-68 19773443 Mamm Genome. 2009 Sep-Oct;20(9-10):573-80 19697081 Oncogene. 2003 Jun 5;22(23):3624-34 12789271 Cell Line Cell Line, Tumor Chromatin Immunoprecipitation CpG Islands DNA Methylation Gene Expression Regulation Histones metabolism Humans MicroRNAs genetics Polymerase Chain Reaction PMC2805718 2009 10 13 2009 12 21 2010 1 13 2010 1 20 6 0 2010 1 20 6 0 2010 5 21 6 0 epublish 10.1371/journal.pone.0008697 20084174 PMC2805718 20080666 2010 02 05 2010 03 05 2014 09 17

1091-6490 107 5 2010 Feb 2 Proc. Natl. Acad. Sci. U.S.A. Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorship. 2183-8 10.1073/pnas.0909896107 Using a multidimensional genomic data set on glioblastoma from The Cancer Genome Atlas, we identified hsa-miR-26a as a cooperating component of a frequently occurring amplicon that also contains CDK4 and CENTG1, two oncogenes that regulate the RB1 and PI3 kinase/AKT pathways, respectively. By integrating DNA copy number, mRNA, microRNA, and DNA methylation data, we identified functionally relevant targets of miR-26a in glioblastoma, including PTEN, RB1, and MAP3K2/MEKK2. We demonstrate that miR-26a alone can transform cells and it promotes glioblastoma cell growth in vitro and in the mouse brain by decreasing PTEN, RB1, and MAP3K2/MEKK2 protein expression, thereby increasing AKT activation, promoting proliferation, and decreasing c-JUN N-terminal kinase-dependent apoptosis. Overexpression of miR-26a in PTEN-competent and PTEN-deficient glioblastoma cells promoted tumor growth in vivo, and it further increased growth in cells overexpressing CDK4 or CENTG1. Importantly, glioblastoma patients harboring this amplification displayed markedly decreased survival. Thus, hsa-miR-26a, CDK4, and CENTG1 comprise a functionally integrated oncomir/oncogene DNA cluster that promotes aggressiveness in human cancers by cooperatively targeting the RB1, PI3K/AKT, and JNK pathways. Kim Hyunsoo H Department of Medicine, Harvard Partners Center for Genetics and Genomics, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Huang Wei W Jiang Xiuli X Pennicooke Brenton B Park Peter J PJ Johnson Mark D MD eng 1U24 CA126554 CA NCI NIH HHS United States R01 GM082798 GM NIGMS NIH HHS United States R01 GM082798 GM NIGMS NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2010 01 13

United States Proc Natl Acad Sci U S A 7505876 0027-8424 0 DNA Primers 0 GTPase-Activating Proteins 0 MIRN26A microRNA, human 0 MicroRNAs 0 Retinoblastoma Protein EC 2.7.11.22 CDK4 protein, human EC 2.7.11.22 Cyclin-Dependent Kinase 4 EC 3.1.3.48 PTEN protein, human EC 3.1.3.67 PTEN Phosphohydrolase EC 3.6.1.- AGAP2 protein, human EC 3.6.1.- GTP-Binding Proteins IM J Biol Chem. 2001 May 4;276(18):14784-90 11278622 Cancer Biol Ther. 2008 Aug;7(8):1288-96 18497571 Proc Natl Acad Sci U S A. 2004 May 4;101(18):6993-8 15118108 Oncogene. 2004 Mar 11;23(10):1863-73 14647432 Am J Pathol. 1999 Jan;154(1):113-8 9916925 Brain Pathol. 1999 Jul;9(3):469-79 10416987 Genes Chromosomes Cancer. 2005 Feb;42(2):193-9 15543620 Cancer Res. 2005 Jul 15;65(14):6029-33 16024602 Genes Chromosomes Cancer. 2006 May;45(5):447-54 16419059 Bioinformatics. 2006 May 15;22(10):1177-82 16446276 Cell Death Differ. 2006 Jul;13(7):1110-22 16273080 J Cell Mol Med. 2007 Jan-Feb;11(1):39-53 17367500 Oncogene. 2007 Jul 26;26(34):4918-27 17297440 Cell Cycle. 2007 Aug 15;6(16):2005-9 17721077 Endocr Relat Cancer. 2007 Sep;14(3):791-8 17914108 Cell Cycle. 2007 Nov 1;6(21):2585-90 17957144 Nucleic Acids Res. 2008 Jan;36(Database issue):D154-8 17991681 Nucleic Acids Res. 2008 Jan;36(Database issue):D149-53 18158296 Cancer Res. 2008 Jan 15;68(2):434-43 18199537 Cell Res. 2008 Mar;18(3):350-9 18270520 Semin Cancer Biol. 2008 Apr;18(2):103-10 18295504 Nature. 2008 Apr 3;452(7187):553-63 18385729 Cancer Cell. 2008 Apr;13(4):355-64 18394558 Cell Cycle. 2008 Mar 15;7(6):759-64 18344688 Nature. 2008 Oct 23;455(7216):1061-8 18772890 Genes Dev. 2009 Jun 1;23(11):1327-37 19487573 Cell. 2003 Dec 26;115(7):787-98 14697198 Clin Cancer Res. 2008 May 1;14(9):2690-5 18451233 Cancer Gene Ther. 2008 Jun;15(6):341-55 18369380 Nucleic Acids Res. 2008 Jul 1;36(Web Server issue):W70-4 18424795 Cancer Res. 2008 May 15;68(10):3566-72 18483236 Animals Base Sequence Brain Neoplasms genetics metabolism Cell Line, Tumor Chromosomes, Human, Pair 12 genetics Cyclin-Dependent Kinase 4 genetics DNA Primers genetics Databases, Nucleic Acid GTP-Binding Proteins genetics GTPase-Activating Proteins genetics Gene Dosage Genomics Glioblastoma genetics metabolism Humans MAP Kinase Signaling System Mice Mice, Nude MicroRNAs antagonists & inhibitors genetics Multigene Family Neoplasm Transplantation Oncogenes PTEN Phosphohydrolase metabolism RNA Interference Retinoblastoma Protein metabolism Signal Transduction Transplantation, Heterologous PMC2836668 2010 1 13 2010 1 19 6 0 2010 1 19 6 0 2010 3 6 6 0 ppublish 0909896107 10.1073/pnas.0909896107 20080666 PMC2836668 22045354 2011 11 02 2012 07 13 2014 09 12

1875-8592 8 4-5 2010-2011 Cancer Biomark The role of chromatin, microRNAs, and tumor stem cells in ovarian cancer. 203-21 10.3233/CBM-2011-0214 The term "epigenetics" refers to DNA sequence-independent events that regulate gene expression, including DNA methylation, modifications to histone proteins, and microRNA-associated post-transcriptional control of protein translation. Epigenetic aberrations are now considered a defining characteristic of numerous human pathologies, including cancer. However, in contrast to DNA sequence mutations, many oncogenic epigenetic modifications are potentially reversible, with studies now showing numerous tumor cell types to possess remarkable phenotypic "plasticity," strongly supporting possible reversion of their malignant status. The "epigenome" of one such malignancy, ovarian cancer, has now been studied in depth, with specific epigenetic alterations correlated with tumor initiation, progression, metastasis, and therapy resistance. Ovarian cancer is the most lethal malignancy of the female reproductive tract, largely due to lack or diagnoses of early-stage disease and the eventual develoment of drug resistance; thus, reliable early detection biomarkers and alternative therapies are urgently needed. In this chapter, we discuss the epigenetics of ovarian cancer, including its likely role in the establishment of "cancer stem cells," i.e., highly tumorigenic progenitor cells believed to be largely or solely responsible for the propagation of malignant, chemotherapy-resistant and metastatic disease. Improved understanding of these gene-regulatory phenomena could likely result in improved detection and survival of this highly destructive malignancy. Balch Curtis C Medical Sciences, Indiana University School of Medicine, Bloomington, IN 47408, USA. Nephew Kenneth P KP eng CA085289 CA NCI NIH HHS United States CA113001 CA NCI NIH HHS United States CA133877 CA NCI NIH HHS United States R01 CA085289 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Netherlands Cancer Biomark 101256509 1574-0153 0 Chromatin 0 MicroRNAs 0 Tumor Markers, Biological IM Animals Chromatin metabolism Epigenesis, Genetic Female Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics metabolism Molecular Targeted Therapy Neoplastic Stem Cells metabolism Ovarian Neoplasms genetics metabolism therapy Tumor Markers, Biological genetics metabolism 2011 11 3 6 0 2010 1 1 0 0 2012 7 14 6 0 ppublish F2G3Q438P53N502P 10.3233/CBM-2011-0214 22045354 21368878 2011 03 03 2011 06 29 2014 09 21

2041-4889 1 2010 Cell Death Dis Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. e105 10.1038/cddis.2010.85 Advanced prostate cancers are known to acquire not only invasive capabilities but also significant resistance to chemotherapy-induced apoptosis. To understand how microRNAs (miRNAs) may contribute to prostate cancer resistance to apoptosis, we compared microRNA expression profiles of a benign prostate cancer cell line WPE1-NA22 and a highly malignant WPE1-NB26 cell line (derived from a common lineage). We found that miR-205 and miR-31 are significantly downregulated in WPE1-NB26 cells, as well as in other cell lines representing advanced-stage prostate cancers. Antiapoptotic genes BCL2L2 (encoding Bcl-w) and E2F6 are identified as the targets of miR-205 and miR-31, respectively. By downregulating Bcl-w and E2F6, miR-205 and miR-31 promote chemotherapeutic agents-induced apoptosis in prostate cancer cells. The promoter region of the miR-205 gene was cloned and was found to be hypermethylated in cell lines derived from advanced prostate cancers, contributing to the downregulation of the gene. Treatment with DNA methylation inhibitor 5-aza-2'-deoxycytidine induced miR-205 expression, downregulated Bcl-w, and sensitized prostate cancer cells to chemotherapy-induced apoptosis. Thus, downregulation of miR-205 and miR-31 has an important role in apoptosis resistance in advanced prostate cancer. Bhatnagar N N Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, 58108, USA. Li X X Padi S K R SK Zhang Q Q Tang M-S MS Guo B B eng CA130062 CA NCI NIH HHS United States P20 RR015566 RR NCRR NIH HHS United States P20 RR015566-10 RR NCRR NIH HHS United States R03 CA130062 CA NCI NIH HHS United States R03 CA130062-02 CA NCI NIH HHS United States RR015566 RR NCRR NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2010 12 09

England Cell Death Dis 101524092 0 Antimetabolites, Antineoplastic 0 Apoptosis Regulatory Proteins 0 BCL2L2 protein, human 0 E2F6 Transcription Factor 0 E2F6 protein, human 0 MIRN205 microRNA, human 0 MIRN31 microRNA, human 0 MicroRNAs 776B62CQ27 decitabine EC 2.1.1.- DNA Modification Methylases M801H13NRU Azacitidine IM J Urol. 2001 Jan;165(1):130-5 11125381 Mol Biol Cell. 2008 Sep;19(9):3691-700 18562691 Genes Dev. 2001 Nov 15;15(22):2922-33 11711427 Science. 2004 Jan 2;303(5654):83-6 14657504 Cell. 2004 Jan 23;116(2):281-97 14744438 Cancer Res. 2004 Mar 15;64(6):1975-86 15026333 Oncogene. 1996 Aug 15;13(4):665-75 8761287 Cancer Res. 1996 Dec 15;56(24):5594-9 8971161 Nature. 2004 Nov 11;432(7014):226-30 15538371 Eur Urol. 2004 Dec;46(6):698-708 15548435 Cancer Res. 2005 Mar 15;65(6):2378-86 15781653 Oncogene. 2005 Apr 7;24(15):2474-82 15735703 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Cell Death Differ. 2007 Apr;14(4):807-17 17096023 Curr Opin Urol. 2007 May;17(3):182-7 17414516 Nature. 2007 Oct 11;449(7163):682-8 17898713 Br J Haematol. 2010 Jan;148(1):69-79 19807731 Cell Death Differ. 2010 Feb;17(2):193-9 19461653 Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13556-61 18768788 Cell Cycle. 2008 Aug 15;7(16):2485-92 18719380 Cell. 2009 Jan 23;136(2):215-33 19167326 Cell Cycle. 2009 Feb 1;8(3):377-82 19177007 Blood. 2009 May 7;113(19):4586-94 19202128 Cancer Res. 2009 May 15;69(10):4443-53 19435910 Mol Cancer Ther. 2009 Jun;8(6):1409-20 19509247 Cell. 2009 Jun 12;137(6):1005-17 19524505 Clin Cancer Res. 2009 Jun 15;15(12):3927-37 19509173 Cancer Res. 2009 Jul 15;69(14):5970-7 19567675 Int J Cancer. 2009 Dec 1;125(11):2737-43 19521961 Blood. 2009 Oct 8;114(15):3255-64 19692702 Prostate. 2001 Apr1;47(1):1-13 11304724 Animals Antimetabolites, Antineoplastic therapeutic use Apoptosis drug effects genetics Apoptosis Regulatory Proteins genetics metabolism physiology Azacitidine analogs & derivatives therapeutic use Cell Line, Tumor DNA Methylation DNA Modification Methylases antagonists & inhibitors Down-Regulation Drug Resistance, Neoplasm genetics E2F6 Transcription Factor genetics metabolism physiology Humans Male Mice MicroRNAs genetics metabolism Promoter Regions, Genetic Prostatic Neoplasms drug therapy genetics metabolism NIHMS257670 PMC3004480 Bcl-w E2F6 apoptosis miR-205 miR-31 prostate cancer 2011 3 4 6 0 2010 1 1 0 0 2011 6 30 6 0 epublish cddis201085 10.1038/cddis.2010.85 21368878 PMC3004480 NIHMS257670 20001799 2009 12 16 2010 02 24 2014 05 23

1744-8301 5 10 2009 Dec Future Oncol Epigenetics of neurological cancers. 1615-29 10.2217/fon.09.132 Epigenetic mechanisms involving DNA methylation, histone modifications and noncoding RNAs regulate and maintain gene-expression states. Similar to genetic mutations, alterations in epigenetic regulation can lead to uncontrolled cell division, tumor initiation and growth, invasiveness and metastasis. Research in brain cancer, particularly gliomas, has uncovered global and gene-specific DNA hypomethylation, local DNA hypermethylation of gene promoters and the de-regulation of microRNA expression. Understanding epigenetic dysregulation in brain cancers has provided new tools for prognostication, as well as suggesting new approaches to therapy. There is significant interest in new sequencing-based technologies that map genetic and epigenetic alterations comprehensively and at high resolution. These methods are being applied to brain tumors, and will better define the contribution of epigenetic defects to tumorigenesis. Fouse Shaun D SD Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA. Costello Joseph F JF eng U01 ES017154 ES NIEHS NIH HHS United States Journal Article Review

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1460-2180 31 1 2010 Jan Carcinogenesis Inflammation and cancer: interweaving microRNA, free radical, cytokine and p53 pathways. 37-49 10.1093/carcin/bgp272 Chronic inflammation and infection are major causes of cancer. There are continued improvements to our understanding of the molecular connections between inflammation and cancer. Key mediators of inflammation-induced cancer include nuclear factor kappa B, reactive oxygen and nitrogen species, inflammatory cytokines, prostaglandins and specific microRNAs. The collective activity of these mediators is largely responsible for either a pro-tumorigenic or anti-tumorigenic inflammatory response through changes in cell proliferation, cell death, cellular senescence, DNA mutation rates, DNA methylation and angiogenesis. As our understanding grows, inflammatory mediators will provide opportunities to develop novel diagnostic and therapeutic strategies. In this review, we provide a general overview of the connection between inflammation, microRNAs and cancer and highlight how our improved understanding of these connections may provide novel preventive, diagnostic and therapeutic strategies to reduce the health burden of cancer. Schetter Aaron J AJ Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Heegaard Niels H H NH Harris Curtis C CC eng Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Review 2009 12 02

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1460-2180 31 1 2010 Jan Carcinogenesis Epigenetics in cancer. 27-36 10.1093/carcin/bgp220 Epigenetic mechanisms are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals. Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation. Global changes in the epigenetic landscape are a hallmark of cancer. The initiation and progression of cancer, traditionally seen as a genetic disease, is now realized to involve epigenetic abnormalities along with genetic alterations. Recent advancements in the rapidly evolving field of cancer epigenetics have shown extensive reprogramming of every component of the epigenetic machinery in cancer including DNA methylation, histone modifications, nucleosome positioning and non-coding RNAs, specifically microRNA expression. The reversible nature of epigenetic aberrations has led to the emergence of the promising field of epigenetic therapy, which is already making progress with the recent FDA approval of three epigenetic drugs for cancer treatment. In this review, we discuss the current understanding of alterations in the epigenetic landscape that occur in cancer compared with normal cells, the roles of these changes in cancer initiation and progression, including the cancer stem cell model, and the potential use of this knowledge in designing more effective treatment strategies. Sharma Shikhar S Department of Urology, Biochemistry and Molecular Biology, USC/Norris Comprehensive Cancer Center Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9181, USA. Kelly Theresa K TK Jones Peter A PA eng CA82422 CA NCI NIH HHS United States CA83867 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Review 2009 09 13

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author reply 1153 14615517 Nucleic Acids Res. 2004;32(3):959-76 14960713 Prostate. 2004 May 1;59(2):177-89 15042618 J Biol Chem. 2004 Apr 23;279(17):17063-9 14761969 Bioinformatics. 2004 May 1;20(7):1170-7 14764558 Proc Natl Acad Sci U S A. 2004 May 11;101(19):7357-62 15123803 Nature. 2004 May 27;429(6990):457-63 15164071 Nat Rev Genet. 2004 Jul;5(7):522-31 15211354 Genes Dev. 2004 Aug 1;18(15):1875-85 15289459 Cell. 2004 Aug 20;118(4):409-18 15315754 Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5076-81 19282482 Oncogene. 2009 Apr 9;28(14):1653-68 19234488 Nat Rev Genet. 2009 May;10(5):295-304 19308066 Epigenetics. 2009 Feb 16;4(2):80-4 19242119 Cancer Res. 2009 May 15;69(10):4277-85 19417133 Mol Cell. 2009 May 15;34(3):271-84 19450526 Mol Cancer Ther. 2009 Jun;8(6):1579-88 19509260 Oncogene. 2009 Jul 9;28(27):2492-501 19448667 Structure. 2008 Feb;16(2):166-79 18275809 Cell. 2008 Mar 7;132(5):887-98 18329373 PLoS Biol. 2008 Mar 18;6(3):e65 18351804 Cell. 2008 Apr 18;133(2):217-22 18423194 Nature. 2008 Nov 6;456(7218):125-9 18815594 Cell. 2008 Nov 14;135(4):649-61 18992931 Mutat Res. 2008 Dec 1;647(1-2):44-51 18691602 Nat Rev Genet. 2009 Jan;10(1):32-42 19065135 Nat Genet. 2009 Jan;41(1):125-9 19098913 Nat Biotechnol. 2009 Jan;27(1):91-7 19122652 Nat Genet. 2009 Feb;41(2):246-50 19151716 Cell. 1999 Oct 29;99(3):247-57 10555141 Genes Dev. 2001 Apr 1;15(7):827-32 11297506 Science. 2001 Aug 10;293(5532):1074-80 11498575 Genes Dev. 2002 Jan 1;16(1):6-21 11782440 Science. 2002 Feb 8;295(5557):1079-82 11834837 Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3740-5 11891299 Nat Genet. 2002 Jun;31(2):175-9 12021783 Nat Rev Genet. 2002 Jun;3(6):415-28 12042769 EMBO J. 2002 Aug 1;21(15):4183-95 12145218 Cancer Res. 2002 Nov 15;62(22):6456-61 12438235 J Biol Chem. 2003 Feb 7;278(6):4035-40 12427740 Cancer Res. 2003 Feb 1;63(3):560-6 12566296 Leukemia. 2003 Feb;17(2):350-8 12592335 Science. 2003 Mar 14;299(5613):1753-5 12637750 Nat Clin Pract Oncol. 2005 Dec;2 Suppl 1:S4-11 16341240 Cancer Res. 2005 Dec 15;65(24):11241-6 16357125 Nat Rev Genet. 2006 Jan;7(1):21-33 16369569 Nature. 2006 Feb 16;439(7078):871-4 16357870 Nat Rev Drug Discov. 2006 Jan;5(1):37-50 16485345 Epigenesis, Genetic Humans MicroRNAs genetics Neoplasms genetics pathology Neoplastic Stem Cells 138 PMC2802667 2009 9 13 2009 9 16 6 0 2009 9 16 6 0 2010 1 12 6 0 ppublish bgp220 10.1093/carcin/bgp220 19752007 PMC2802667 19631700 2010 03 12 2010 04 21

0006-3002 1803 1 2010 Jan Biochim. Biophys. Acta Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. 3-19 10.1016/j.bbamcr.2009.07.004 Matrix metalloproteinases (MMPs) are a large family of zinc-endopeptidases which play important roles in multiple physiological and pathological processes. These enzymes are widely distributed in all kingdoms of life and have likely evolved from a single-domain protein which underwent successive rounds of duplication, gene fusion and exon shuffling events to generate the multidomain architecture and functional diversity currently exhibited by MMPs. Proper regulation of these enzymes is required to prevent their unwanted activity in a variety of disorders, including cancer, arthritis and cardiovascular diseases. Multiple hormones, cytokines and growth factors are able to induce MMP expression, although the tissue specificity of the diverse family members is mainly achieved by the combination of different transcriptional control mechanisms. The integration of multiple signaling pathways, coupled with the cooperation between several cis-regulatory elements found at the MMP promoters facilitates the strict spatiotemporal control of MMP transcriptional activity. Additionally, epigenetic mechanisms, such as DNA methylation or histone acetylation, may also contribute to MMP regulation. Likewise, post-transcriptional regulatory processes including mRNA stability, protein translational efficiency, and microRNA-based mechanisms have been recently described as modulators of MMP gene expression. Parallel studies have led to the identification of MMP polymorphisms and mutations causally implicated in the development of different genetic diseases. These genomic analyses have been further extended through the generation of animal models of gain- or loss-of-function for MMPs which have allowed the identification of novel functions for these enzymes and the establishment of causal relationships between MMP dysregulation and development of different human diseases. Further genomic studies of MMPs, including functional analysis of gene regulation and generation of novel animal models will help to answer the multiple questions still open in relation to a family of enzymes which strongly influence multiple events in life and disease. Copyright 2009 Elsevier B.V. All rights reserved. Fanjul-Fernández Miriam M Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain. Folgueras Alicia R AR Cabrera Sandra S López-Otín Carlos C eng Journal Article Research Support, Non-U.S. Gov't Review 2009 07 23

Netherlands Biochim Biophys Acta 0217513 0006-3002 EC 3.4.24.- Matrix Metalloproteinases IM Animals Disease Epigenesis, Genetic Evolution, Molecular Gene Expression Regulation, Enzymologic Matrix Metalloproteinases classification genetics metabolism Mice Models, Animal 232 2009 3 24 2009 7 11 2009 7 14 2009 7 23 2009 7 28 9 0 2009 7 28 9 0 2010 4 22 6 0 ppublish S0167-4889(09)00187-6 10.1016/j.bbamcr.2009.07.004 19631700 19601887 2009 07 15 2009 09 22

1389-5575 9 8 2009 Jul Mini Rev Med Chem MicroRNA regulatory network in human colorectal cancer. 921-6 Epigenetic modifications include DNA methylation, histone modifications, and noncoding RNAs containing microRNAs (miRNA). miRNAs are small noncoding RNAs that are 21 to 25 nt in length; they downregulate gene expression during cell development, cell proliferation, cell differentiation, and apoptosis. They play a critical role in human carcinogenesis. Presently, evidences show that miRNAs participate as oncogenic miRNAs or tumor suppressors in the developmental and physiological processes of human colorectal cancer (CRC). Disturbed miRNA expression may be attributable to a mechanism involving multiple factors. In this review, we focus on the colorectal miRNA expression profile and further discuss the miRNA regulatory network involved in the tumorigenesis of human CRC. We, thus, hope to open up new avenues for anticancer therapy based on the epigenetic regulation of miRNA. Tang Jie-Ting JT Shanghai Institute of Digestive Disease, Renji Hospital, Shanghai 200001, China. Fang Jing-Yuan JY eng Journal Article Review

Netherlands Mini Rev Med Chem 101094212 1389-5575 0 MicroRNAs IM Animals Colorectal Neoplasms genetics metabolism Epigenesis, Genetic Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics metabolism 46 2009 7 16 9 0 2009 7 16 9 0 2009 9 23 6 0 ppublish 19601887 19549897 2009 07 16 2009 09 25 2014 09 24

1538-7445 69 14 2009 Jul 15 Cancer Res. Xenoestrogen-induced epigenetic repression of microRNA-9-3 in breast epithelial cells. 5936-45 10.1158/0008-5472.CAN-08-4914 Early exposure to xenoestrogens may predispose to breast cancer risk later in adult life. It is likely that long-lived, self-regenerating epithelial progenitor cells are more susceptible to these exposure injuries over time and transmit the injured memory through epigenetic mechanisms to their differentiated progeny. Here, we used progenitor-containing mammospheres as an in vitro exposure model to study this epigenetic effect. Expression profiling identified that, relative to control cells, 9.1% of microRNAs (82 of 898 loci) were altered in epithelial progeny derived from mammospheres exposed to a synthetic estrogen, diethylstilbestrol. Repressive chromatin marks, trimethyl Lys27 of histone H3 (H3K27me3) and dimethyl Lys9 of histone H3 (H3K9me2), were found at a down-regulated locus, miR-9-3, in epithelial cells preexposed to diethylstilbestrol. This was accompanied by recruitment of DNA methyltransferase 1 that caused an aberrant increase in DNA methylation of its promoter CpG island in mammosphere-derived epithelial cells on diethylstilbestrol preexposure. Functional analyses suggest that miR-9-3 plays a role in the p53-related apoptotic pathway. Epigenetic silencing of this gene, therefore, reduces this cellular function and promotes the proliferation of breast cancer cells. Promoter hypermethylation of this microRNA may be a hallmark for early breast cancer development, and restoration of its expression by epigenetic and microRNA-based therapies is another viable option for future treatment of this disease. Hsu Pei-Yin PY Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA. Deatherage Daniel E DE Rodriguez Benjamin A T BA Liyanarachchi Sandya S Weng Yu-I YI Zuo Tao T Liu Joseph J Cheng Alfred S L AS Huang Tim H-M TH eng R01 CA069065 CA NCI NIH HHS United States R01 CA069065 CA NCI NIH HHS United States R01 CA069065-11 CA NCI NIH HHS United States R01 CA069065-12 CA NCI NIH HHS United States R01 ES017594 ES NIEHS NIH HHS United States R01 ES017594-01 ES NIEHS NIH HHS United States U01 ES015986 ES NIEHS NIH HHS United States U01 ES015986 ES NIEHS NIH HHS United States U01 ES015986-03 ES NIEHS NIH HHS United States U54 CA113001 CA NCI NIH HHS United States U54 CA113001 CA NCI NIH HHS United States U54 CA113001-04 CA NCI NIH HHS United States U54 CA113001-05 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2009 06 23

United States Cancer Res 2984705R 0008-5472 0 Hydroxamic Acids 0 MicroRNAs 3X2S926L3Z trichostatin A 731DCA35BT Diethylstilbestrol 776B62CQ27 decitabine M801H13NRU Azacitidine IM Oncogene. 2008 Dec 4;27(53):6707-19 18806827 Reprod Toxicol. 2007 Apr-May;23(3):297-307 17046196 Steroids. 2000 May;65(5):227-51 10751636 Cancer Res. 2006 Dec 15;66(24):11954-66 17178894 Cancer Epidemiol Biomarkers Prev. 2006 Aug;15(8):1509-14 16896041 Endocrinology. 2008 Jan;149(1):339-45 17884941 Cancer Res. 2008 Mar 15;68(6):1786-96 18339859 Cancer Res. 2008 Jul 15;68(14):5753-9 18632628 J Cell Biol. 2008 Jul 28;182(2):327-40 18644889 Carcinogenesis. 2008 Jul;29(7):1459-65 18499701 Nat Cell Biol. 2001 Jan;3(1):15-23 11146621 J Air Waste Manag Assoc. 2001 Apr;51(4):499-513 11321907 Annu Rev Cell Dev Biol. 2001;17:387-403 11687494 Science. 2002 May 31;296(5573):1642-4 12040178 Nat Rev Genet. 2002 Jun;3(6):415-28 12042769 Oncogene. 2002 Aug 12;21(35):5380-7 12154400 Science. 2002 Nov 1;298(5595):1039-43 12351676 Cancer Causes Control. 2002 Oct;13(8):753-8 12420954 Genes Dev. 2003 May 15;17(10):1253-70 12756227 Clin Cancer Res. 2003 Jun;9(6):1980-9 12796359 Environ Health Perspect. 2003 Jun;111(8):1007-19 12826474 Environ Sci Technol. 2003 Oct 15;37(20):4543-53 14594359 Breast Cancer Res Treat. 2003 Oct;81(3):177-86 14620913 J Steroid Biochem Mol Biol. 2003 Oct;87(1):1-25 14630087 J Mol Endocrinol. 2004 Jun;32(3):987-95 15171727 Curr Opin Genet Dev. 2004 Apr;14(2):155-64 15196462 Med Clin North Am. 1974 Jul;58(4):793-810 4276416 Cancer Res. 2004 Nov 15;64(22):8184-92 15548683 Cancer Res. 2005 Aug 15;65(16):7065-70 16103053 Nat Rev Genet. 2005 Aug;6(8):597-610 16136652 Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15785-90 16243968 N Engl J Med. 2006 Jan 19;354(3):270-82 16421368 Endocrinology. 2006 Jun;147(6 Suppl):S11-7 16690809 Endocrinology. 2006 Jun;147(6 Suppl):S18-24 16690811 Cancer Res. 2006 Jun 1;66(11):5624-32 16740699 Mol Cell Endocrinol. 2006 Jul 25;254-255:179-86 16781053 Cancer Res. 2006 Aug 1;66(15):7793-800 16885383 Cell Cycle. 2009 Mar 1;8(5):712-5 19221490 Azacitidine analogs & derivatives pharmacology Breast cytology metabolism Cell Line, Tumor Cells, Cultured CpG Islands genetics DNA Methylation Diethylstilbestrol pharmacology Epigenesis, Genetic drug effects Epithelial Cells cytology drug effects metabolism Fluorescent Antibody Technique Gene Expression drug effects Gene Expression Profiling Gene Regulatory Networks Humans Hydroxamic Acids pharmacology MicroRNAs genetics Models, Biological Oligonucleotide Array Sequence Analysis Reverse Transcriptase Polymerase Chain Reaction Transfection NIHMS186945 PMC2855843 2009 6 23 2009 6 25 9 0 2009 6 25 9 0 2009 9 26 6 0 ppublish 0008-5472.CAN-08-4914 10.1158/0008-5472.CAN-08-4914 19549897 PMC2855843 NIHMS186945 19521961 2009 10 05 2009 11 06 2013 11 21

1097-0215 125 11 2009 Dec 1 Int. J. Cancer Epigenetic regulation of microRNA expression in colorectal cancer. 2737-43 10.1002/ijc.24638 In the last years, microRNAs (miRNA) have emerged as new molecular players involved in carcinogenesis. Deregulation of miRNAs expression has been shown in different human cancer but the molecular mechanism underlying the alteration of miRNA expression is unknown. To identify tumor-supressor miRNAs silenced through aberrant epigenetic events in colorectal cancer (CRC), we used a sequential approach. We first identified 5 miRNAs down-regulated in patient with colorectal cancer samples and located around/on a CpG island. Treatment with a DNA methyltransferase inhibitor and a HDAC inhibitor restored expression of 3 of the 5 microRNAs (hsa-miR-9, hsa-miR-129 and hsa-miR-137) in 3 CRC cell lines. Expression of hsa-miR-9 was inversely correlated with methylation of their promoter regions as measure by MSP and bisulphate sequencing. Further, methylation of the hsa-miR-9-1, hsa-miR-129-2 and hsa-miR-137 CpG islands were frequently observed in CRC cell lines and in primary CRC tumors, but not in normal colonic mucosa. Finally, methylation of hsa-miR-9-1 was associated with the presence of lymph node metastasis. In summary, our results aid in the understanding of miRNA gene regulation showing that aberrant DNA methylation and histone modifications work together to induce silencing of miRNAs in CRC. Bandres Eva E Division of Oncology, Laboratory of Pharmacogenomics, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarra, Spain. ebandres@unav.es Agirre Xabier X Bitarte Nerea N Ramirez Natalia N Zarate Ruth R Roman-Gomez Jose J Prosper Felipe F Garcia-Foncillas Jesus J eng Journal Article Research Support, Non-U.S. Gov't

United States Int J Cancer 0042124 0020-7136 0 Antimetabolites, Antineoplastic 0 Histone Deacetylase Inhibitors 0 Histones 0 MicroRNAs 0 Phenylbutyrates 4593-90-2 3-phenylbutyric acid EC 3.5.1.98 Histone Deacetylases M801H13NRU Azacitidine IM Acetylation Antimetabolites, Antineoplastic pharmacology Azacitidine pharmacology Cell Line, Tumor Colorectal Neoplasms genetics metabolism pathology CpG Islands DNA Methylation Epigenesis, Genetic Gene Expression Regulation, Neoplastic Gene Silencing Histone Deacetylase Inhibitors Histone Deacetylases metabolism Histones metabolism Humans Lymphatic Metastasis MicroRNAs genetics metabolism Phenylbutyrates pharmacology Promoter Regions, Genetic Tumor Cells, Cultured 2009 6 13 9 0 2009 6 13 9 0 2009 11 7 6 0 ppublish 10.1002/ijc.24638 19521961 19503096 2009 07 30 2009 08 11 2013 11 21

1476-5594 28 30 2009 Jul 30 Oncogene Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells. 2738-44 10.1038/onc.2009.140 Epigenetic therapy using DNA methylation inhibitors and histone deacetylase (HDAC) inhibitors has clinical promise for the treatment of human malignancies. To investigate roles of microRNAs (miRNAs) on epigenetic therapy of gastric cancer, the miRNA expression profile was analysed in human gastric cancer cells treated with 5-aza-2'-deoxycytidine (5-Aza-CdR) and 4-phenylbutyric acid (PBA). miRNA microarray analysis shows that most of miRNAs activated by 5-Aza-CdR and PBA in gastric cancer cells are located at Alu repeats on chromosome 19. Analyses of chromatin modification show that DNA demethylation and HDAC inhibition at Alu repeats activates silenced miR-512-5p by RNA polymerase II. In addition, activation of miR-512-5p by epigenetic treatment induces suppression of Mcl-1, resulting in apoptosis of gastric cancer cells. These results suggest that chromatin remodeling at Alu repeats plays critical roles in the regulation of miRNA expression and that epigenetic activation of silenced Alu-associated miRNAs could be a novel therapeutic approach for gastric cancer. Saito Y Y Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan. Suzuki H H Tsugawa H H Nakagawa I I Matsuzaki J J Kanai Y Y Hibi T T eng Journal Article Research Support, Non-U.S. Gov't 2009 06 08

England Oncogene 8711562 0950-9232 0 Histone Deacetylase Inhibitors 0 MicroRNAs 0 Myeloid Cell Leukemia Sequence 1 Protein 0 Phenylbutyrates 0 Proto-Oncogene Proteins c-bcl-2 776B62CQ27 decitabine 7WY7YBI87E 4-phenylbutyric acid EC 2.7.7.- DNA Polymerase II EC 2.7.7.- DNA Polymerase III M801H13NRU Azacitidine IM Alu Elements Apoptosis Azacitidine analogs & derivatives pharmacology Cell Line, Tumor Chromatin Assembly and Disassembly Chromosomes, Human, Pair 19 DNA Methylation DNA Polymerase II physiology DNA Polymerase III physiology Down-Regulation Epigenesis, Genetic Histone Deacetylase Inhibitors Humans MicroRNAs physiology Myeloid Cell Leukemia Sequence 1 Protein Phenylbutyrates pharmacology Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors Stomach Neoplasms genetics pathology therapy 2009 6 08 2009 6 9 9 0 2009 6 9 9 0 2009 8 12 9 0 ppublish onc2009140 10.1038/onc.2009.140 19503096 19395242 2009 05 04 2009 07 21 2012 10 09

1873-569X 54 3 2009 Jun J. Dermatol. Sci. Aberrant DNA methylation in skin diseases. 143-9 10.1016/j.jdermsci.2009.01.009 Epigenetic mechanisms are involved in regulating cell growth and differentiation without inducing changes in the gene sequence. The main epigenetic mechanisms include DNA methylation, histone modification, and microRNA. Recent studies indicate that aberrant DNA methylation is a common feature of many human disorders, including cancer, autoimmune diseases, heart diseases, skin diseases, and others. Skin diseases comprise various diseases that have a complex etiology and pathogenesis, including genetics and acquired factors such as environment and diet. These acquired factors often have pathogenic effects through modification of DNA and histones, of which DNA methylation is the most common mechanism. Aberrant DNA methylation has been demonstrated in skin diseases, including skin tumors and autoimmune-related skin disorders. Herein, we review the role of DNA methylation in the pathogenesis of skin diseases. Li Yaping Y Department of Dermatology and Epigenetic Research Center, Second Xiangya Hospital, Central South University, Changsha, Hunan, China. Sawalha Amr H AH Lu Qianjin Q eng P30 AR053483 AR NIAMS NIH HHS United States Journal Article Research Support, Non-U.S. Gov't Review 2009 04 22

Netherlands J Dermatol Sci 9011485 0923-1811 0 Histones IM Animals Autoimmune Diseases genetics metabolism DNA Methylation genetics physiology Epigenesis, Genetic genetics physiology Histones genetics metabolism Humans Skin Neoplasms genetics metabolism 60 2008 12 31 2009 1 16 2009 1 29 2009 4 22 2009 4 28 9 0 2009 4 28 9 0 2009 7 22 9 0 ppublish S0923-1811(09)00061-9 10.1016/j.jdermsci.2009.01.009 19395242 19232437 2009 11 03 2010 01 25

1872-9142 47 1 2009 Nov Mol. Immunol. Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis. 12-8 10.1016/j.molimm.2009.01.010 Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the progressive and irreversible destruction of joints. RA remains an incurable condition, although a new class of drugs, biologicals, have made a major breakthrough in targeting and/or eliminating the immune cells, including T cells, B cells and monocytes/macrophages from the joints. That we cannot (yet?) cure the disease is most likely due to the lack of therapeutic targeting the endogenously activated RA synovial fibroblasts (RASF). Most interestingly, RASF express Toll-like receptors (TLRs) 1-6 rendering them prone to activation by exogenous and endogenous TLR ligands and resulting in the production of numerous powerful chemokines and cytokines. These factors are responsible for the repopulation of immune cells in the joints after ceasing cell depleting therapies. To characterize the molecular mechanisms of synovial activation, a new approach studying the epigenetic characteristics of RASF has been recently undertaken. Thereby, the pattern of histone acetylation, DNA methylation and gene expression regulating microRNA are being explored. Since auto-antibodies have the most predictive and diagnostic value for RA, it is challenging to study more comprehensively the contribution of auto-antibodies to the disease. A new screening technique, serological analysis of recombinant human cDNA expression library (SEREX), adapted from cancer research allowed for the identification of novel auto-antibodies in RA, including anti-serpin E2 auto-antibodies. The serpin E2 auto-antibodies were found to inhibit the activity of serpin E2 and have potentially a functional role in the disease. The recent findings in the field of innate immunity, epigenetics and autoimmunity related to the pathogenesis of RA are in the scope of this review. Maciejewska Rodrigues Hanna H Center of Experimental Rheumatology, University Hospital Zurich/Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Gloriastrasse 23-25, CH-8091 Zurich, Switzerland. hanna.maciejewska@usz.ch Jüngel Astrid A Gay Renate E RE Gay Steffen S eng Journal Article Research Support, Non-U.S. Gov't 2009 02 15

England Mol Immunol 7905289 0161-5890 0 Autoantibodies IM Animals Arthritis, Rheumatoid etiology genetics immunology Autoantibodies Autoimmunity Epigenesis, Genetic immunology Humans Immunity, Innate 2008 10 21 2009 1 6 2009 1 8 2009 2 15 2009 2 24 9 0 2009 2 24 9 0 2010 1 26 6 0 ppublish S0161-5890(09)00036-4 10.1016/j.molimm.2009.01.010 19232437 19232136 2009 05 12 2009 06 01 2013 08 28

1471-2199 10 2009 BMC Mol. Biol. Transcriptional inhibiton of Hoxd4 expression by miRNA-10a in human breast cancer cells. 12 10.1186/1471-2199-10-12 Small noncoding RNAs (ncRNAs), including short interfering RNAs (siRNAs) and microRNAs (miRNAs), can silence genes at the transcriptional, post-transcriptional or translational level 12. Here, we show that microRNA-10a (miR-10a) targets a homologous DNA region in the promoter region of the hoxd4 gene and represses its expression at the transcriptional level. Mutational analysis of the miR-10a sequence revealed that the 3' end of the miRNA sequence is the most critical element for the silencing effect. MicroRNA-10a-induced transcriptional gene inhibition requires the presence of Dicer and Argonautes 1 and 3, and it is related to promoter associated noncoding RNAs. Bisulfite sequencing analysis showed that the reduced hoxd4 expression was accompanied by de novo DNA methylation at the hoxd4 promoter. We further demonstrated that trimethylation of histone 3 lysine 27 (H3K27me3) is involved in the miR-10a-induced hoxd4 transcriptional gene silence. In conclusion, our results demonstrate that miR-10a can regulate human gene expression in a transcriptional manner, and indicate that endogenous small noncoding RNA-induced control of transcription may be a potential system for expressional regulation in human breast cancer cells. Tan Yuliang Y National laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, PR China. tyl@moon.ibp.ac.cn Zhang Bo B Wu Tao T Skogerbø Geir G Zhu Xiaopeng X Guo Xiangqian X He Shunmin S Chen Runsheng R eng Journal Article Research Support, Non-U.S. Gov't 2009 02 22

England BMC Mol Biol 100966983 1471-2199 0 Argonaute Proteins 0 EIF2C1 protein, human 0 EIF2C3 protein, human 0 Eukaryotic Initiation Factor-2 0 Eukaryotic Initiation Factors 0 HOXD1 protein, human 0 Homeodomain Proteins 0 MicroRNAs EC 3.1.26.3 Ribonuclease III IM Science. 2003 Jan 31;299(5607):716-9 12522258 Science. 2001 Aug 3;293(5531):834-8 11452083 Cell. 2004 Jan 23;116(2):281-97 14744438 Science. 2004 Aug 27;305(5688):1289-92 15297624 Nat Genet. 2004 Oct;36(10):1079-83 15361871 Science. 2005 Feb 11;307(5711):932-5 15705854 Cell. 2005 Mar 11;120(5):635-47 15766527 Nature. 2005 Jun 9;435(7043):834-8 15944708 Trends Genet. 2005 Jul;21(7):370-3 15908035 Nat Genet. 2005 Aug;37(8):906-10 16025112 Nat Rev Genet. 2005 Dec;6(12):893-904 16341070 RNA. 2006 Feb;12(2):256-62 16373483 Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6629-34 16618927 Nat Struct Mol Biol. 2006 Sep;13(9):793-7 16936726 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17337-42 17085592 Nat Struct Mol Biol. 2007 Mar;14(3):200-7 17310250 Nature. 2007 Jun 28;447(7148):1130-4 17554337 Cell. 2007 Jun 29;129(7):1311-23 17604720 Genes Dev. 2007 Jul 1;21(13):1603-8 17606638 Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12422-7 17640892 RNA. 2007 Sep;13(9):1397-401 17652135 Nucleic Acids Res. 2007;35(15):5154-64 17660190 Nature. 2007 Oct 11;449(7163):682-8 17898713 Genes Dev. 2008 Jan 1;22(1):8-13 18172160 Genes Dev. 2008 Jan 1;22(1):14-9 18172161 Genes Dev. 2008 Jan 1;22(1):26-36 18172163 Curr Top Microbiol Immunol. 2008;320:211-24 18268846 Nat Rev Mol Cell Biol. 2008 Mar;9(3):219-30 18270516 Nat Struct Mol Biol. 2008 Mar;15(3):268-79 18311151 Nat Struct Mol Biol. 2008 Mar;15(3):259-67 18311153 Cancer Res. 2008 Apr 15;68(8):2570-5 18413723 Mol Cell. 2008 May 23;30(4):460-71 18498749 Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16230-5 18852463 Nat Genet. 2003 Jun;34(2):157-65 12730694 Argonaute Proteins Breast Neoplasms metabolism Cell Line, Tumor DNA Methylation Eukaryotic Initiation Factor-2 metabolism Eukaryotic Initiation Factors metabolism Gene Expression Regulation, Neoplastic Gene Silencing HeLa Cells Homeodomain Proteins metabolism Humans MicroRNAs metabolism Promoter Regions, Genetic Ribonuclease III metabolism PMC2680403 2008 8 19 2009 2 22 2009 2 22 2009 2 24 9 0 2009 2 24 9 0 2009 6 2 9 0 epublish 1471-2199-10-12 10.1186/1471-2199-10-12 19232136 PMC2680403 19165869 2009 03 30 2009 04 14

1097-0215 124 10 2009 May 15 Int. J. Cancer DNA methylation of microRNA genes in gastric mucosae of gastric cancer patients: its possible involvement in the formation of epigenetic field defect. 2367-74 10.1002/ijc.24219 Accumulation of aberrant DNA methylation in normal-appearing gastric mucosae, mostly induced by H. pylori infection, is now known to be deeply involved in predisposition to gastric cancers (epigenetic field defect), and silencing of protein-coding genes has been analyzed so far. In this study, we aimed to clarify the involvement of microRNA (miRNA) gene silencing in the field defect. First, we selected three miRNA genes as methylation-silenced after analysis of six candidate "methylation-silenced" tumor-suppressor miRNA genes. Methylation levels of the three genes (miR-124a-1, miR-124a-2 and miR-124a-3) were quantified in 56 normal gastric mucosae of healthy volunteers (28 volunteers with H. pylori and 28 without), 45 noncancerous gastric mucosae of gastric cancer patients (29 patients with H. pylori and 16 without), and 28 gastric cancer tissues (13 intestinal and 15 diffuse types). Among the healthy volunteers, individuals with H. pylori had 7.8-13.1-fold higher methylation levels than those without (p < 0.001). Among individuals without H. pylori, noncancerous gastric mucosae of gastric cancer patients had 7.2-15.5-fold higher methylation levels than gastric mucosae of healthy volunteers (p < 0.005). Different from protein-coding genes, individuals with past H. pylori infection retained similar methylation levels to those with current infection. In cancer tissues, methylation levels were highly variable, and no difference was observed between intestinal and diffuse histological types. This strongly indicated that methylation-silencing of miRNA genes, in addition to that of protein-coding genes, contributed to the formation of a field defect for gastric cancers. (c) 2008 Wiley-Liss, Inc. Ando Takayuki T Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan. Yoshida Takeichi T Enomoto Shotaro S Asada Kiyoshi K Tatematsu Masae M Ichinose Masao M Sugiyama Toshiro T Ushijima Toshikazu T eng Journal Article Research Support, Non-U.S. Gov't

United States Int J Cancer 0042124 0020-7136 0 MicroRNAs IM Cell Line, Tumor DNA Methylation Epigenesis, Genetic Female Gastric Mucosa metabolism microbiology Gene Silencing Helicobacter pylori isolation & purification Humans Male MicroRNAs genetics Reverse Transcriptase Polymerase Chain Reaction Stomach Neoplasms genetics microbiology pathology 2009 1 24 9 0 2009 1 24 9 0 2009 4 15 9 0 ppublish 10.1002/ijc.24219 19165869 19152082 2009 01 19 2009 06 26

1006-9305 52 1 2009 Jan Sci. China, C, Life Sci. Current progress in epigenetic research for hepatocarcinomagenesis. 31-42 10.1007/s11427-009-0014-7 Hepatocellular carcinoma is the main type of primary liver cancer, and also one of the most malignant tumors. At present, the pathogenesis mechanisms of liver cancer are not entirely clear. It has been shown that inactivation of tumor suppressor genes and activation of oncogenes play a significant role in carcinogenesis, caused by the genetic and epigenetic aberrance. In the past, people generally thought that genetic mutation is a key event of tumor pathogenesis, and somatic mutation of tumor suppressor genes is in particular closely associated with oncogenesis. With deeper understanding of tumors in recent years, increasing evidence has shown that epigenetic silencing of those genes, as a result of aberrant hypermethylation of CpG islands in promoters and histone modification, is essential to carcinogenesis and metastasis. The term epigenetics refers to heritable changes in gene expression caused by regulation mechanisms, other than changes in the underlying DNA sequence. Specific epigenetic processes include DNA methylation, genome imprinting, chromotin remodeling, histone modification and microRNA regulations. This paper reviews recent epigenetics research progress in the hepatocellular carcinoma study, and tries to depict the relationships between hepatocellular carcinomagenesis and DNA methylation as well as microRNA regulation. Huang Jian J National Human Genome Research Center at Shanghai-Ministry of Science and Technology to build a healthy and disease Genomics Laboratory, Shanghai, 201203, China. huangj@chgc.sh.cn eng Journal Article Research Support, Non-U.S. Gov't Review 2009 01 19

China Sci China C Life Sci 9611809 1006-9305 0 MicroRNAs IM Animals Carcinoma, Hepatocellular genetics metabolism Cell Transformation, Neoplastic genetics metabolism DNA Methylation Epigenesis, Genetic genetics Humans Liver Neoplasms genetics metabolism MicroRNAs genetics 70 2008 10 3 2008 10 8 2009 1 19 2009 1 20 9 0 2009 1 20 9 0 2009 6 27 9 0 ppublish 10.1007/s11427-009-0014-7 19152082 19116145 2009 01 28 2009 02 27 2013 11 21

1090-2104 379 3 2009 Feb 13 Biochem. Biophys. Res. Commun. Epigenetic therapy upregulates the tumor suppressor microRNA-126 and its host gene EGFL7 in human cancer cells. 726-31 10.1016/j.bbrc.2008.12.098 Studies have shown that aberrant expression of miRNAs is involved in the initiation and progression of cancer, and several miRNAs have been characterized as tumor suppressors or oncogenes. Restoring the expression of tumor suppressor genes by epigenetic therapy has great potential in cancer treatment and it has been shown that some miRNAs can be directly regulated from their own promoters by epigenetic alterations in cancer cells. However, the majority of miRNAs are located within intronic regions of transcription units and it was unclear if intronic miRNAs can also be epigenetically regulated. Here we show that the tumor suppressor miR-126, which is located within an intron of the EGFL7 gene, is downregulated in cancer cell lines and in primary bladder and prostate tumors. Mature miR-126 can be generated from three different transcripts of EGFL7 with each one having its own promoter. Interestingly, miR-126 and one of the transcripts of EGFL7 that has a CpG island promoter are concomitantly upregulated in cancer cell lines by inhibitors of DNA methylation and histone deacetylation. These findings suggest that epigenetic changes can control the expression of tumor suppressor intronic miRNAs by directly controlling their host genes. Thus, epigenetic therapy not only directly activates miRNAs from their own promoters, but also activates intronic miRNAs together with their host genes. This reveals an additional mechanism and anticancer effect of epigenetic therapy. Saito Yoshimasa Y Department of Urology, Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089-9181, USA. Friedman Jeffrey M JM Chihara Yoshitomo Y Egger Gerda G Chuang Jody C JC Liang Gangning G eng P30 CA 014089 CA NCI NIH HHS United States R01 CA 82422 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2008 12 29

United States Biochem Biophys Res Commun 0372516 0006-291X 0 Antineoplastic Agents 0 EGFL7 protein, human 0 Endothelial Growth Factors 0 MIRN126 microRNA, human 0 MicroRNAs 0 Phenylbutyrates 776B62CQ27 decitabine 7WY7YBI87E 4-phenylbutyric acid M801H13NRU Azacitidine IM Antineoplastic Agents pharmacology therapeutic use Azacitidine analogs & derivatives pharmacology therapeutic use Cell Line, Tumor Endothelial Growth Factors genetics Epigenesis, Genetic drug effects Gene Expression Regulation, Neoplastic drug effects Genes, Tumor Suppressor Humans Male MicroRNAs genetics Neoplasms genetics Phenylbutyrates pharmacology therapeutic use Promoter Regions, Genetic Prostatic Neoplasms genetics Up-Regulation Urinary Bladder Neoplasms genetics 2008 12 8 2008 12 17 2008 12 29 2009 1 1 9 0 2009 1 1 9 0 2009 2 28 9 0 ppublish S0006-291X(08)02504-7 10.1016/j.bbrc.2008.12.098 19116145 19033256 2009 03 02 2009 05 19 2013 08 29

1464-3804 24 2 2009 Mar Mutagenesis Environmental exposure measurement in cancer epidemiology. 117-25 10.1093/mutage/gen061 Environmental exposures, used in the broadest sense of lifestyle, infections, radiation, natural and man-made chemicals and occupation, are a major cause of human cancer. However, the precise contribution of specific risk factors and their interaction, both with each other and with genotype, continues to be difficult to elucidate. This is partially due to limitations in accurately measuring exposure with the subsequent risk of misclassification. One of the primary challenges of molecular cancer epidemiology therefore is to improve exposure assessment. Progress has been made with biomarkers such as carcinogens and their metabolites, DNA and protein adducts and mutations measured in various tissues and body fluids. Nevertheless, much remains to be accomplished in order to establish aetiology and provide the evidence base for public health decisions. This review considers some of the principles behind the application of exposure biomarkers in cancer epidemiology. It also demonstrates how the same biomarkers can contribute both to establishing the biological plausibility of associations between exposure and disease and be valuable endpoints in intervention studies. The potential of new technologies such as transcriptomics, proteomics and metabonomics to provide a step change in environmental exposure assessment is discussed. An increasing recognition of the role of epigenetic changes in carcinogenesis presents a fresh challenge as alterations in DNA methylation, histone modification and microRNA in response to environmental exposures demand a new generation of exposure biomarker. The overall importance of this area of research is brought into sharp relief by the large prospective cohort studies (e.g. UK Biobank) which need accurate exposure measurement in order to shed light on the complex gene:environment interactions underlying common chronic disorders including cancer. It is suggested that a concerted effort is now required, with appropriate funding, to develop and validate the required exposure assessment methodology before these cohorts come to maturity. Wild Christopher P CP Molecular Epidemiology Unit, Centre for Epidemiology and Biostatistics, Leeds Institute of Genetics, Health and Therapeutics, LIGHT Laboratories, University of Leeds, Leeds, UK. c.p.wild@leeds.ac.uk eng ES06052 ES NIEHS NIH HHS United States Journal Article Research Support, N.I.H., Extramural Review 2008 11 25

England Mutagenesis 8707812 0267-8357 0 Biological Markers IM Mutat Res. 2007 May-Jun;635(2-3):105-17 17257890 J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jun 15;853(1-2):1-9 17418649 Lancet. 2007 Jun 16;369(9578):1980-2 17574079 Cancer. 2007 Nov 1;110(9):2019-26 17876837 Environ Health. 2007;6:38 18045465 Clin Cancer Res. 2008 Jan 1;14(1):97-107 18172258 Nat Rev Cancer. 2008 Mar;8(3):205-11 18235448 N Engl J Med. 2008 Mar 13;358(11):1148-59 18337604 PLoS Genet. 2007 Nov;3(11):e207 18039032 Nature. 2008 May 15;453(7193):396-400 18425110 Nat Genet. 2008 Jun;40(6):768-75 18454148 Br J Cancer. 2008 Jun 17;98(12):1881-5 18542062 Carcinogenesis. 2008 May;29(5):977-83 18332047 Mutat Res. 2001 Sep 1;480-481:317-31 11506824 Cancer Res. 2001 Sep 15;61(18):6708-12 11559540 Mutat Res. 2001 Oct;489(1):1-16 11673087 Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14601-6 11724948 Food Addit Contam. 2001 Dec;18(12):1088-93 11761119 Cancer Epidemiol Biomarkers Prev. 2002 May;11(5):459-66 12010860 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11 27 9 0 2009 5 20 9 0 2008 11 27 9 0 ppublish gen061 10.1093/mutage/gen061 19033256 PMC2720689 18768788 2008 09 10 2008 09 30 2013 08 29

1091-6490 105 36 2008 Sep 9 Proc. Natl. Acad. Sci. U.S.A. A microRNA DNA methylation signature for human cancer metastasis. 13556-61 10.1073/pnas.0803055105 MicroRNAs (miRNAs) are small, noncoding RNAs that can contribute to cancer development and progression by acting as oncogenes or tumor suppressor genes. Recent studies have also linked different sets of miRNAs to metastasis through either the promotion or suppression of this malignant process. Interestingly, epigenetic silencing of miRNAs with tumor suppressor features by CpG island hypermethylation is also emerging as a common hallmark of human tumors. Thus, we wondered whether there was a miRNA hypermethylation profile characteristic of human metastasis. We used a pharmacological and genomic approach to reveal this aberrant epigenetic silencing program by treating lymph node metastatic cancer cells with a DNA demethylating agent followed by hybridization to an expression microarray. Among the miRNAs that were reactivated upon drug treatment, miR-148a, miR-34b/c, and miR-9 were found to undergo specific hypermethylation-associated silencing in cancer cells compared with normal tissues. The reintroduction of miR-148a and miR-34b/c in cancer cells with epigenetic inactivation inhibited their motility, reduced tumor growth, and inhibited metastasis formation in xenograft models, with an associated down-regulation of the miRNA oncogenic target genes, such as C-MYC, E2F3, CDK6, and TGIF2. Most important, the involvement of miR-148a, miR-34b/c, and miR-9 hypermethylation in metastasis formation was also suggested in human primary malignancies (n = 207) because it was significantly associated with the appearance of lymph node metastasis. Our findings indicate that DNA methylation-associated silencing of tumor suppressor miRNAs contributes to the development of human cancer metastasis. Lujambio Amaia A Cancer Epigenetics Laboratory, Spanish National Cancer Research Center, Melchor Fernández Almagro 3, 28029 Madrid, Spain. Calin George A GA Villanueva Alberto A Ropero Santiago S Sánchez-Céspedes Montserrat M Blanco David D Montuenga Luis M LM Rossi Simona S Nicoloso Milena S MS Faller William J WJ Gallagher William M WM Eccles Suzanne A SA Croce Carlo M CM Esteller Manel M eng Journal Article Research Support, Non-U.S. Gov't 2008 09 03

United States Proc Natl Acad Sci U S A 7505876 0027-8424 0 MicroRNAs IM Cell. 2004 Jan 23;116(2):281-97 14744438 In Silico Biol. 2003;3(3):235-40 12954087 Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9740-4 15210942 J Cell Physiol. 1965 Dec;66(3):325-33 5884360 Proc Natl Acad Sci U S A. 1998 Jun 9;95(12):6870-5 9618505 RNA. 2004 Dec;10(12):1957-66 15525708 Nature. 2005 Jun 9;435(7043):834-8 15944708 Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):13968-73 16172399 RNA. 2005 Nov;11(11):1737-44 16244135 Cell Cycle. 2006 Feb;5(3):266-70 16410727 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Nat Rev Cancer. 2006 Apr;6(4):259-69 16557279 Cancer Cell. 2006 Jun;9(6):435-43 16766263 Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9136-41 16754881 Cell Cycle. 2006 Oct;5(19):2220-2 17012846 Cell. 2006 Nov 17;127(4):679-95 17110329 Cancer Res. 2007 Feb 15;67(4):1424-9 17308079 Nat Rev Genet. 2007 Apr;8(4):286-98 17339880 Nat Genet. 2007 May;39(5):582-3 17460676 PLoS Comput Biol. 2007 Mar 9;3(3):e37 17352530 Cell Cycle. 2007 Jun 15;6(12):1455-9 17581274 Nature. 2007 Jun 28;447(7148):1130-4 17554337 Cancer Res. 2007 Sep 15;67(18):8433-8 17823410 Nature. 2007 Oct 11;449(7163):682-8 17898713 Cancer Treat Res. 2007;135:39-53 17953407 Nat Rev Cancer. 2007 Nov;7(11):819-22 17914404 Proc Natl Acad Sci U S A. 2007 Nov 6;104(45):17719-24 17965236 Cancer Cell. 2007 Nov;12(5):414-8 17996645 Cancer Biol Ther. 2007 Aug;6(8):1284-8 17660710 J Pathol. 2008 Jan;214(1):17-24 17948228 Nature. 2008 Jan 10;451(7175):147-52 18185580 Nat Cell Biol. 2008 Feb;10(2):202-10 18193036 Hepatology. 2008 Mar;47(3):897-907 18176954 Cancer Res. 2008 Jun 1;68(11):4123-32 18519671 Nat Rev Genet. 2004 Jul;5(7):522-31 15211354 Recent Results Cancer Res. 2000;157:55-81 10857162 Biochem Biophys Res Commun. 2000 Sep 16;276(1):264-70 11006116 Nat Rev Cancer. 2003 Jun;3(6):453-8 12778135 Future Oncol. 2008 Dec;4(6):775-7 19086843 Animals Cell Line, Tumor CpG Islands genetics DNA Methylation Disease Progression Down-Regulation Gene Expression Regulation, Neoplastic Gene Silencing Humans Male Mice Mice, Nude MicroRNAs genetics Neoplasm Metastasis genetics Oligonucleotide Array Sequence Analysis Transcription, Genetic genetics PMC2528872 2008 9 3 2008 9 5 9 0 2008 10 1 9 0 2008 9 5 9 0 ppublish 0803055105 10.1073/pnas.0803055105 18768788 PMC2528872 18677110 2008 08 08 2008 11 24 2014 09 12

1551-4005 7 15 2008 Aug Cell Cycle Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation. 2427-33 The cellular response to Nutlin-3, a small-molecule inhibitor of the p53 repressor MDM2, varies widely among human cancer-derived cell types. Whereas HCT116 colorectal carcinoma cells display sustained cell cycle arrest, BV173 leukemia cells undergo rapid apoptosis and other cell lines show an intermediate response. We found that the expression of the p53 target genes p21, 14-3-3sigma and the microRNA miR-34a correlates tightly with the cell fate choice adopted. All three genes were strongly induced in arresting cells, but silenced in cells undergoing Nutlin-3-induced apoptosis. In contrast, key apoptotic p53 target genes were equally expressed in arresting and apoptotic cells. Interestingly, we establish that miR-34a cooperates with p21 and 14-3-3sigma to override the apoptotic signals generated by p53 activation. Strikingly, p53 binding to chromatin and p53-mediated recruitment of certain coactivators to all three target loci does not vary among cell types. Instead, the cell type-specific silencing of these genes is due to enhanced p21 mRNA degradation, 14-3-3sigma promoter DNA methylation and reduced processing of the miR-34a primary transcript. Thus, p53-independent events regulating expression of protein-coding genes and microRNAs within the network can define the cellular outcome of p53 activation. París Ramiro R Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, Colorado 80309-0347, USA. Henry Ryan E RE Stephens Sarah J SJ McBryde Meagan M Espinosa Joaquín M JM eng (5-FY05-1217 PHS HHS United States CM05054 CM NCI NIH HHS United States R01 CA117907 CA NCI NIH HHS United States R01 CA117907-01 CA NCI NIH HHS United States R01 CA117907-02 CA NCI NIH HHS United States R01 CA117907-03 CA NCI NIH HHS United States R01- CA117907 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2008 06 09

United States Cell Cycle 101137841 1551-4005 0 14-3-3 Proteins 0 CDKN1A protein, human 0 Cyclin-Dependent Kinase Inhibitor p21 0 Imidazoles 0 MIRN34 microRNA, human 0 MicroRNAs 0 Piperazines 0 Tumor Suppressor Protein p53 0 nutlin 3 IM Mol Cell. 2007 Jul 6;27(1):121-33 17612495 J Biol Chem. 2006 Nov 3;281(44):33036-44 16905769 Cancer Cell. 2007 Aug;12(2):171-85 17692808 Cancer Cell. 2007 Nov;12(5):414-8 17996645 Cell Cycle. 2007 Nov 1;6(21):2594-8 17957141 Science. 2008 Apr 4;320(5872):97-100 18292307 Oncogene. 2008 Jul 3;27(29):4013-23 18278067 Mol Cell Biol. 2003 Jul;23(14):4991-5004 12832484 Nat Rev Cancer. 2002 Aug;2(8):594-604 12154352 Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1888-93 16443686 Mol Cell. 2003 Oct;12(4):1015-27 14580351 Science. 2004 Feb 6;303(5659):844-8 14704432 Genes Dev. 2000 Jul 1;14(13):1584-8 10887152 Nature. 2000 Nov 16;408(6810):307-10 11099028 Mol Cell. 2001 Jul;8(1):57-69 11511360 Biochem Soc Trans. 2001 Nov;29(Pt 6):684-8 11709054 EMBO J. 2004 Aug 4;23(15):3092-102 15257295 J Biol Chem. 1989 Mar 5;264(7):4021-7 2521857 Cell. 1993 Nov 19;75(4):817-25 8242752 Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6 8790415 Mol Cell. 1997 Dec;1(1):3-11 9659898 DNA Cell Biol. 2005 Apr;24(4):264-9 15812243 Nat Struct Mol Biol. 2006 Jan;13(1):13-21 16369484 Genes Dev. 2006 Jan 15;20(2):125-31 16418478 Genes Dev. 2006 Mar 1;20(5):601-12 16510875 Cancer Res. 2006 Mar 15;66(6):3169-76 16540668 Curr Opin Genet Dev. 2006 Apr;16(2):203-8 16503132 RNA. 2006 Jul;12(7):1161-7 16738409 Genes Dev. 2006 Aug 15;20(16):2202-7 16882971 Int J Mol Med. 2006 Oct;18(4):547-57 16964403 J Biol Chem. 2006 Nov 3;281(44):33030-5 16905541 Mol Cell. 2007 Jul 20;27(2):214-27 17643371 14-3-3 Proteins genetics Apoptosis drug effects genetics Carcinoma genetics pathology Colorectal Neoplasms genetics pathology Cyclin-Dependent Kinase Inhibitor p21 genetics Gene Expression Regulation Gene Silencing physiology HCT116 Cells Humans Imidazoles pharmacology MicroRNAs physiology Models, Biological Piperazines pharmacology Signal Transduction genetics Tumor Cells, Cultured Tumor Suppressor Protein p53 metabolism physiology NIHMS227966 PMC2926973 2008 6 9 2008 8 5 9 0 2008 12 17 9 0 2008 8 5 9 0 ppublish 6420 18677110 PMC2926973 NIHMS227966 18645025 2008 07 22 2008 09 08 2013 11 21

1535-7163 7 7 2008 Jul Mol. Cancer Ther. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. 2152-9 10.1158/1535-7163.MCT-08-0021 Many chemotherapy regiments are successfully used to treat breast cancer; however, often breast cancer cells develop drug resistance that usually leads to a relapse and worsening of prognosis. We have shown recently that epigenetic changes such as DNA methylation and histone modifications play an important role in breast cancer cell resistance to chemotherapeutic agents. Another mechanism of gene expression control is mediated via the function of small regulatory RNA, particularly microRNA (miRNA); its role in cancer cell drug resistance still remains unexplored. In the present study, we investigated the role of miRNA in the resistance of human MCF-7 breast adenocarcinoma cells to doxorubicin (DOX). Here, we for the first time show that DOX-resistant MCF-7 cells (MCF-7/DOX) exhibit a considerable dysregulation of the miRNAome profile and altered expression of miRNA processing enzymes Dicer and Argonaute 2. The mechanistic link of miRNAome deregulation and the multidrug-resistant phenotype of MCF-7/DOX cells was evidenced by a remarkable correlation between specific miRNA expression and corresponding changes in protein levels of their targets, specifically those ones that have a documented role in cancer drug resistance. Furthermore, we show that microRNA-451 regulates the expression of multidrug resistance 1 gene. More importantly, transfection of the MCF-7/DOX-resistant cells with microRNA-451 resulted in the increased sensitivity of cells to DOX, indicating that correction of altered expression of miRNA may have significant implications for therapeutic strategies aiming to overcome cancer cell resistance. Kovalchuk Olga O Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada T1K 3M4. olga.kovalchuk@uleth.ca Filkowski Jody J Meservy James J Ilnytskyy Yaroslav Y Tryndyak Volodymyr P VP Chekhun Vasyl' F VF Pogribny Igor P IP eng Journal Article Research Support, Non-U.S. Gov't

United States Mol Cancer Ther 101132535 1535-7163 0 Argonaute Proteins 0 EIF2C2 protein, human 0 Eukaryotic Initiation Factor-2 0 MIRN451 microRNA, human 0 MicroRNAs 0 P-Glycoprotein 80168379AG Doxorubicin EC 3.1.26.3 Ribonuclease III IM Argonaute Proteins Base Sequence Breast Neoplasms enzymology genetics pathology Cell Line, Tumor Doxorubicin pharmacology Drug Resistance, Neoplasm drug effects Drug Screening Assays, Antitumor Eukaryotic Initiation Factor-2 metabolism Gene Expression Regulation, Neoplastic drug effects Humans MicroRNAs genetics metabolism Molecular Sequence Data P-Glycoprotein genetics metabolism Ribonuclease III metabolism 2008 7 23 9 0 2008 9 9 9 0 2008 7 23 9 0 ppublish 7/7/2152 10.1158/1535-7163.MCT-08-0021 18645025 18593897 2008 07 02 2008 08 05 2011 04 21

1538-7445 68 13 2008 Jul 1 Cancer Res. miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer. 5004-8 10.1158/0008-5472.CAN-08-0180 Expression levels of estrogen receptor (ER) alpha govern estrogen-dependent growth, response to endocrine therapy, and prognosis in ERalpha-positive breast cancer. Multiple mechanisms involved in altering ERalpha gene expression in breast cancer have been identified, including ERalpha gene amplification as well as transcriptional silencing by DNA methylation of CpG islands within the ERalpha promoter and mutations within the open reading frame of ERalpha. However, expression levels of ERalpha in breast cancer tissues differ widely among patients, and frequently change during disease progression and in response to systemic therapies. Recent evidence has shown that microRNA mutations or misexpression correlate with various human cancers, and miR-206 is reported to decrease endogenous ERalpha mRNA and protein levels in human MCF-7 breast cancer cells via two specific target sites within the 3'-untranslated region of the human ERalpha transcript. In this study, we show for the first time that miR-206 expression is markedly decreased in ERalpha-positive human breast cancer tissues assayed by quantitative reverse transcription-PCR analysis. Moreover, we observe that miR-206 expression is inversely correlated with ERalpha but not ERbeta mRNA expression in breast cancer tissues. Transfection experiments revealed that introduction of miR-206 into estrogen-dependent MCF-7 breast cancer cells inhibits cell growth in a dose- and time-dependent manner. Our results suggest that miR-206 could be a novel candidate for endocrine therapy that targets only ERalpha in breast cancer. Kondo Naoto N Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. Toyama Tatsuya T Sugiura Hiroshi H Fujii Yoshitaka Y Yamashita Hiroko H eng Journal Article

United States Cancer Res 2984705R 0008-5472 0 Antineoplastic Agents, Hormonal 0 Estrogen Receptor alpha 0 MicroRNAs 0 RNA, Messenger 0 estrogen receptor alpha, human 0 mirn206 microRNA, rat IM Adult Aged Aged, 80 and over Antineoplastic Agents, Hormonal therapeutic use Breast Neoplasms drug therapy genetics pathology Carcinoma, Ductal, Breast drug therapy genetics pathology Cell Proliferation Down-Regulation Estrogen Receptor alpha genetics metabolism Female Gene Expression Regulation, Neoplastic Humans MicroRNAs genetics Middle Aged Neoplasm Invasiveness Neoplasms, Hormone-Dependent drug therapy genetics pathology RNA, Messenger metabolism Transfection Tumor Cells, Cultured 2008 7 3 9 0 2008 8 6 9 0 2008 7 3 9 0 ppublish 68/13/5004 10.1158/0008-5472.CAN-08-0180 18593897 18185590 2008 01 10 2008 02 05 2014 09 22

1476-4687 451 7175 2008 Jan 10 Nature Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. 202-6 10.1038/nature06468 Tumour suppressor genes (TSGs) inhibiting normal cellular growth are frequently silenced epigenetically in cancer. DNA methylation is commonly associated with TSG silencing, yet mutations in the DNA methylation initiation and recognition machinery in carcinogenesis are unknown. An intriguing possible mechanism for gene regulation involves widespread non-coding RNAs such as microRNA, Piwi-interacting RNA and antisense RNAs. Widespread sense-antisense transcripts have been systematically identified in mammalian cells, and global transcriptome analysis shows that up to 70% of transcripts have antisense partners and that perturbation of antisense RNA can alter the expression of the sense gene. For example, it has been shown that an antisense transcript not naturally occurring but induced by genetic mutation leads to gene silencing and DNA methylation, causing thalassaemia in a patient. Here we show that many TSGs have nearby antisense RNAs, and we focus on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukaemia. We found an inverse relation between p15 antisense (p15AS) and p15 sense expression in leukaemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer-independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus, natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in TSG silencing in tumorigenesis. Yu Wenqiang W Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, USA. Gius David D Onyango Patrick P Muldoon-Jacobs Kristi K Karp Judith J Feinberg Andrew P AP Cui Hengmi H eng R37 CA054358 CA NCI NIH HHS United States R37 CA054358-18 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural

England Nature 0410462 0028-0836 0 Cyclin-Dependent Kinase Inhibitor p15 0 Heterochromatin 0 RNA, Antisense EC 3.1.26.3 Ribonuclease III IM Nature. 2002 Jul 11;418(6894):244-51 12110901 Mol Cell. 2007 Jun 8;26(5):611-23 17560368 Nat Genet. 2003 Jun;34(2):157-65 12730694 Nat Biotechnol. 2004 Jan;22(1):104-8 14704709 Nat Rev Cancer. 2004 Feb;4(2):143-53 14732866 Nat Rev Cancer. 2003 Dec;3(12):895-902 14737120 Cell. 2004 Apr 2;117(1):69-81 15066283 Nature. 2004 Jul 8;430(6996):161-4 15241403 Cancer Cell. 2004 Oct;6(4):361-71 15488759 Oncogene. 2007 Jan 4;26(1):77-90 16799634 Leukemia. 2003 Sep;17(9):1762-4 12970776 Science. 2000 Dec 22;290(5500):2306-9 11125145 Nature. 1994 Apr 21;368(6473):753-6 8152487 Mol Cell Biol. 1997 May;17(5):2458-67 9111314 Nat Genet. 1999 Feb;21(2):163-7 9988266 Science. 2005 Mar 25;307(5717):1976-8 15731405 Nat Genet. 2005 Aug;37(8):906-10 16025112 Science. 2005 Sep 2;309(5740):1564-6 16141073 Nat Rev Genet. 2006 Jan;7(1):21-33 16369569 RNA. 2006 Feb;12(2):256-62 16373483 Cell. 2006 Jun 30;125(7):1215-20 16814704 Cancer Res. 2002 Nov 15;62(22):6442-6 12438232 Animals Cell Differentiation Cell Line, Tumor Cyclin-Dependent Kinase Inhibitor p15 biosynthesis genetics DNA Methylation Embryonic Stem Cells cytology metabolism Epigenesis, Genetic Gene Expression Regulation, Neoplastic genetics Genes, Tumor Suppressor Heterochromatin genetics metabolism Leukemia genetics Mice Models, Genetic Promoter Regions, Genetic genetics RNA, Antisense genetics metabolism Ribonuclease III genetics metabolism NIHMS113858 PMC2743558 2007 8 14 2007 11 09 2008 1 11 9 0 2008 2 6 9 0 2008 1 11 9 0 ppublish nature06468 10.1038/nature06468 18185590 PMC2743558 NIHMS113858 17890317 2007 10 03 2007 11 27 2013 09 03

0027-8424 104 40 2007 Oct 2 Proc. Natl. Acad. Sci. U.S.A. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. 15805-10 MicroRNAs (miRNAs) are small, noncoding RNAs that regulate expression of many genes. Recent studies suggest roles of miRNAs in carcinogenesis. We and others have shown that expression profiles of miRNAs are different in lung cancer vs. normal lung, although the significance of this aberrant expression is poorly understood. Among the reported down-regulated miRNAs in lung cancer, the miRNA (miR)-29 family (29a, 29b, and 29c) has intriguing complementarities to the 3'-UTRs of DNA methyltransferase (DNMT)3A and -3B (de novo methyltransferases), two key enzymes involved in DNA methylation, that are frequently up-regulated in lung cancer and associated with poor prognosis. We investigated whether miR-29s could target DNMT3A and -B and whether restoration of miR-29s could normalize aberrant patterns of methylation in non-small-cell lung cancer. Here we show that expression of miR-29s is inversely correlated to DNMT3A and -3B in lung cancer tissues, and that miR-29s directly target both DNMT3A and -3B. The enforced expression of miR-29s in lung cancer cell lines restores normal patterns of DNA methylation, induces reexpression of methylation-silenced tumor suppressor genes, such as FHIT and WWOX, and inhibits tumorigenicity in vitro and in vivo. These findings support a role of miR-29s in epigenetic normalization of NSCLC, providing a rationale for the development of miRNA-based strategies for the treatment of lung cancer. Fabbri Muller M Department of Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, and College of Pharmacy, Ohio State University, Columbus, OH 43210, USA. Garzon Ramiro R Cimmino Amelia A Liu Zhongfa Z Zanesi Nicola N Callegari Elisa E Liu Shujun S Alder Hansjuerg H Costinean Stefan S Fernandez-Cymering Cecilia C Volinia Stefano S Guler Gulnur G Morrison Carl D CD Chan Kenneth K KK Marcucci Guido G Calin George A GA Huebner Kay K Croce Carlo M CM eng R01 CA120516 CA NCI NIH HHS United States R01 CA132453 CA NCI NIH HHS United States Journal Article Research Support, N.I.H., Extramural 2007 09 21

United States Proc Natl Acad Sci U S A 7505876 0027-8424 0 DNA, Neoplasm 0 MicroRNAs 0 RNA, Neoplasm EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA methyltransferase 3A EC 2.1.1.37 DNA methyltransferase 3B IM Cell. 1999 Oct 29;99(3):247-57 10555141 Nat Genet. 2005 May;37(5):495-500 15806104 Chembiochem. 2002 Apr 2;3(4):274-93 11933228 Cancer Res. 2002 Sep 1;62(17):4992-5 12208751 Int J Cancer. 2003 Jul 1;105(4):527-32 12712445 Clin Cancer Res. 2003 Oct 1;9(12):4415-22 14555514 Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15611-6 16223882 Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):15785-90 16243968 Nucleic Acids Res. 2005;33(20):e179 16314309 J Cell Physiol. 2006 Mar;206(3):611-5 16222700 Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2257-61 16461460 Curr Biol. 2006 Mar 7;16(5):460-71 16458514 Cancer Cell. 2006 Mar;9(3):189-98 16530703 Nat Rev Cancer. 2006 Apr;6(4):259-69 16557279 J Mol Biol. 2006 May 12;358(4):983-96 16564540 Cancer. 2006 Sep 1;107(5):1042-9 16888795 Nat Rev Cancer. 2006 Nov;6(11):857-66 17060945 Trends Mol Med. 2006 Dec;12(12):580-7 17071139 Cancer Res. 2006 Dec 15;66(24):11590-3 17178851 Nucleic Acids Res. 2007 Jan;35(Database issue):D149-55 17108354 Lung Cancer. 2007 Feb;55(2):205-13 17140695 CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66 17237035 Cell. 2007 Feb 23;128(4):683-92 17320506 Nucleic Acids Res. 2007;35(5):e31 17264127 Pediatr Res. 2007 May;61(5 Pt 2):24R-29R 17413852 Oncogene. 2007 Sep 13;26(42):6133-40 17404574 Cancer Res. 2003 Nov 1;63(21):7089-93 14612500 Cell. 2003 Dec 26;115(7):787-98 14697198 Cell. 2004 Jan 23;116(2):281-97 14744438 Cancer Res. 2004 May 1;64(9):3137-43 15126351 Nucleic Acids Res. 1997 Nov 15;25(22):4666-73 9358180 Cancer Res. 1999 May 15;59(10):2302-6 10344733 PLoS Biol. 2004 Nov;2(11):e363 15502875 Oncogene. 2005 Feb 24;24(9):1625-33 15674328 Curr Opin Genet Dev. 2005 Apr;15(2):200-5 15797203 Mol Carcinog. 2002 Mar;33(3):163-71 11870882 Carcinoma, Non-Small-Cell Lung enzymology genetics DNA (Cytosine-5-)-Methyltransferase genetics DNA Methylation DNA, Neoplasm genetics Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Lung enzymology Lung Neoplasms enzymology genetics mortality MicroRNAs genetics Prognosis RNA, Neoplasm genetics Survival Analysis PMC2000384 2007 9 21 2007 9 25 9 0 2007 12 6 9 0 2007 9 25 9 0 ppublish 0707628104 10.1073/pnas.0707628104 17890317 PMC2000384 17700064 2007 08 29 2008 07 21 2013 11 21

1551-4005 6 16 2007 Aug 15 Cell Cycle Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications and aberrant microRNA expression. 2010-8 Breast cancer is the most common malignancy in women continuing to rise worldwide. Breast cancer emerges through a multi-step process, encompassing progressive changes from a normal cell to hyperplasia (with and without atypia), carcinoma in situ, invasive carcinoma, and metastasis. In the current study, we analyzed the morphological changes and alterations of DNA methylation, histone methylation and microRNA expression during estradiol-17beta (E(2))-induced mammary carcinogenesis in female August Copenhagen Irish (ACI) rats. E(2)-induced breast carcinogenesis in ACI rats provides a physiologically relevant and genetically defined animal model for studying human sporadic breast cancer. The pattern of morphological changes in mammary glands during E(2)-induced carcinogenesis was characterized by transition from normal appearing alveolar and ductular hyperplasia to focal hyperplastic areas of atypical glands and ducts accompanied by a rapid and sustained loss of global DNA methylation, LINE-1 hypomethylation, loss of histone H3 lysine 9 and histone H4 lysine 20 trimethylation, and altered microRNAs expression. More importantly, these alterations in the mammary tissue occurred after six weeks of E(2)-treatment, whereas the atypical hyperplasia, which represents a putative precursor lesion to mammary carcinoma in this model, was detected only after twelve weeks of exposure, demonstrating clearly that these events are directly associated with the effects of E(2) and are not a consequence of the preexisting preneoplastic lesions. The results of this study show that deregulation of cellular epigenetic processes plays a crucial role in the mechanism of E(2)-induced mammary carcinogenesis in ACI rats, especially in the tumor initiation process. Kovalchuk Olga O Department of Biological Sciences, University of Lethbridge, Lethbridge, Canada. olga.kovalchuk@uleth.ca Tryndyak Volodymyr P VP Montgomery Beverly B Boyko Alex A Kutanzi Kristy K Zemp Franz F Warbritton Alan R AR Latendresse John R JR Kovalchuk Igor I Beland Frederick A FA Pogribny Igor P IP eng Journal Article Research Support, Non-U.S. Gov't 2007 06 06

United States Cell Cycle 101137841 1551-4005 0 Estrogens 0 Histones 0 MicroRNAs 4TI98Z838E Estradiol EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase IM Animals Blotting, Western Cell Transformation, Neoplastic chemically induced genetics metabolism DNA (Cytosine-5-)-Methyltransferase metabolism DNA Methylation drug effects Electrophoresis, Polyacrylamide Gel Estradiol toxicity Estrogens toxicity Female Gene Expression Regulation drug effects Histones metabolism Mammary Neoplasms, Experimental chemically induced genetics metabolism Methylation drug effects MicroRNAs genetics Rats 2007 6 6 2007 8 19 9 0 2008 7 22 9 0 2007 8 19 9 0 ppublish 4549 17700064 17660710 2007 12 06 2008 02 28 2010 05 21

1555-8576 6 8 2007 Aug Cancer Biol. Ther. DNA methylation regulates MicroRNA expression. 1284-8 MicroRNAs (miRNAs), an important class of small regulatory molecules for gene expression, are transcribed by RNA polymerase II. But little is known about the mechanisms that control miRNA expression. Comparing miRNA expression profiles between colon cancer cell line HCT 116 and its derivative, DNA methyltransferase 1 and 3b (DNMT1 and DNMT3b) double knockout cell line, we found that the expression of about 10% miRNAs was regulated by DNA methylation. In addition, neither 5-aza-2'-deoxycytidine treatment nor deletion of DNMT1 alone recapitulated miRNA expression profile seen in the double knockout cell line, suggesting that miRNA expression was tightly controlled by DNA methylation and partial methylation reduction was not sufficient for miRNA reexpression. We also found that HOXA3 and HOXD10 were putative targets of mir-10a, one of the differentially expressed miRNAs that is located in HOX gene cluster. Han Liangfeng L Predoctoral Training Program in Human Genetics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Witmer P Dane PD Casey Emily E Valle David D Sukumar Saraswati S eng Journal Article Research Support, U.S. Gov't, Non-P.H.S. 2007 05 24

United States Cancer Biol Ther 101137842 1538-4047 0 HOXA3 protein, human 0 Homeodomain Proteins 0 MicroRNAs 0 Transcription Factors 145420-66-2 HOXD10 protein, human EC 2.1.1.37 DNA (Cytosine-5-)-Methyltransferase EC 2.1.1.37 DNA (cytosine-5-)-methyltransferase 1 EC 2.1.1.37 DNA methyltransferase 3B IM Cell Line, Tumor Colonic Neoplasms genetics metabolism CpG Islands genetics DNA (Cytosine-5-)-Methyltransferase genetics metabolism DNA Methylation Gene Expression Regulation, Neoplastic Homeodomain Proteins genetics Humans MicroRNAs metabolism Transcription Factors genetics 2007 5 24 2007 7 31 9 0 2008 2 29 9 0 2007 7 31 9 0 ppublish 4486 17660710 17596910 2007 07 16 2007 10 03

0890-6238 24 1 2007 Jul Reprod. Toxicol. A new paradigm in toxicology and teratology: altering gene activity in the absence of DNA sequence variation. 20-30 'Epigenetics' is a heritable phenomenon without change in primary DNA sequence. In recent years, this field has attracted much attention as more epigenetic controls of gene activities are being discovered. Such epigenetic controls ensue from an interplay of DNA methylation, histone modifications, and RNA-mediated pathways from non-coding RNAs, notably silencing RNA (siRNA) and microRNA (miRNA). Although epigenetic regulation is inherent to normal development and differentiation, this can be misdirected leading to a number of diseases including cancer. All the same, many of the processes can be reversed offering a hope for epigenetic therapies such as inhibitors of enzymes controlling epigenetic modifications, specifically DNA methyltransferases, histone deacetylases, and RNAi therapeutics. 'In utero' or early life exposures to dietary and environmental exposures can have a profound effect on our epigenetic code, the so-called 'epigenome', resulting in birth defects and diseases developed later in life. Indeed, examples are accumulating in which environmental exposures can be attributed to epigenetic causes, an encouraging edge towards greater understanding of the contribution of epigenetic influences of environmental exposures. Routine analysis of epigenetic modifications as part of the mechanisms of action of environmental contaminants is in order. There is, however, an explosion of research in the field of epigenetics and to keep abreast of these developments could be a challenge. In this paper, we provide an overview of epigenetic mechanisms focusing on recent reviews and studies to serve as an entry point into the realm of 'environmental epigenetics'. Reamon-Buettner Stella Marie SM Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai Fuchs Strasse 1, 30625 Hannover, Germany. Borlak Jürgen J eng Journal Article Review 2007 05 22

United States Reprod Toxicol 8803591 0890-6238 0 Antineoplastic Agents 0 Environmental Pollutants 0 Histones IM Abnormalities, Drug-Induced genetics metabolism Animals Antineoplastic Agents pharmacology therapeutic use DNA Methylation Environmental Pollutants toxicity Epigenesis, Genetic drug effects Gene Expression Regulation, Developmental drug effects Gene Expression Regulation, Neoplastic drug effects Genomic Imprinting Histones metabolism Humans Neoplasms drug therapy genetics metabolism RNA Interference Teratology trends Toxicology trends X Chromosome Inactivation 85 2007 4 27 2007 4 30 2007 5 8 2007 5 22 2007 6 29 9 0 2007 10 4 9 0 2007 6 29 9 0 ppublish S0890-6238(07)00178-5 10.1016/j.reprotox.2007.05.002 17596910 17308078 2007 02 19 2007 03 15 2008 12 05

0008-5472 67 4 2007 Feb 15 Cancer Res. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. 1419-23 MicroRNAs (miRNAs) are small noncoding RNAs that repress their target mRNAs by complementary base pairing and induction of the RNA interference pathway. It has been shown that miRNA expression can be regulated by DNA methylation and it has been suggested that altered miRNA gene methylation might contribute to human tumorigenesis. In this study, we show that the human let-7a-3 gene on chromosome 22q13.31 is associated with a CpG island. Let-7a-3 belongs to the archetypal let-7 miRNA gene family and was found to be methylated by the DNA methyltransferases DNMT1 and DNMT3B. The gene was heavily methylated in normal human tissues but hypomethylated in some lung adenocarcinomas. Let-7a-3 hypomethylation facilitated epigenetic reactivation of the gene and elevated expression of let-7a-3 in a human lung cancer cell line resulted in enhanced tumor phenotypes and oncogenic changes in transcription profiles. Our results thus identify let-7a-3 as an epigenetically regulated miRNA gene with oncogenic function and suggest that aberrant miRNA gene methylation might contribute to the human cancer epigenome. Brueckner Bodo B Divisions of Epigenetics and Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Stresemann Carlo C Kuner Ruprecht R Mund Cora C Musch Tanja T Meister Michael M Sültmann Holger H Lyko Frank F eng Journal Article Research Support, Non-U.S. Gov't

United States Cancer Res 2984705R 0008-5472 0 MicroRNAs 0 mirnlet7 microRNA, human IM Adenocarcinoma genetics Adenoma genetics Colorectal Neoplasms genetics DNA Methylation HCT116 Cells Humans Lung Neoplasms genetics MicroRNAs genetics metabolism Neoplasms genetics Oncogenes Transfection 2007 2 20 9 0 2007 3 16 9 0 2007 2 20 9 0 ppublish 67/4/1419 10.1158/0008-5472.CAN-06-4074 17308078