Epigenetics in cancer.

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.

[1]  P. Jones,et al.  Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment , 1977, Nature.

[2]  A. Feinberg,et al.  Hypomethylation distinguishes genes of some human cancers from their normal counterparts , 1983, Nature.

[3]  A. Riggs,et al.  5-methylcytosine, gene regulation, and cancer. , 1983, Advances in cancer research.

[4]  F. Watt,et al.  Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. , 1988, Genes & development.

[5]  T. R. Hebbes,et al.  A direct link between core histone acetylation and transcriptionally active chromatin. , 1988, The EMBO journal.

[6]  G. Prendergast,et al.  Methylation-sensitive sequence-specific DNA binding by the c-Myc basic region. , 1991, Science.

[7]  A. Feinberg,et al.  Relaxation of imprinted genes in human cancer , 1993, Nature.

[8]  M. Eccles,et al.  Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour , 1993, Nature.

[9]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[10]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[11]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[12]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.

[13]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[14]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[15]  G. Seydoux,et al.  PIE-1 is a bifunctional protein that regulates maternal and zygotic gene expression in the embryonic germ line of Caenorhabditis elegans. , 2001, Genes & development.

[16]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[17]  Q. Feng,et al.  The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes. , 2001, Genes & development.

[18]  Hong Duan,et al.  Role for DNA methylation in the control of cell type–specific maspin expression , 2002, Nature Genetics.

[19]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[20]  Peter A. Jones,et al.  Histone H3-lysine 9 methylation is associated with aberrant gene silencing in cancer cells and is rapidly reversed by 5-aza-2'-deoxycytidine. , 2002, Cancer research.

[21]  S. Minucci,et al.  Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor , 2002, Science.

[22]  Daiya Takai,et al.  Comprehensive analysis of CpG islands in human chromosomes 21 and 22 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  R. Roberts,et al.  Co‐operation and communication between the human maintenance and de novo DNA (cytosine‐5) methyltransferases , 2002, The EMBO journal.

[24]  A. Bird DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[25]  M. Grever,et al.  Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells , 2003, Leukemia.

[26]  J. Issa,et al.  Comment on "Chromosomal Instability and Tumors Promoted by DNA Hypomethylation" and "Induction of Tumors in Mice by Genomic Hypomethylation" , 2003, Science.

[27]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Tony Kouzarides,et al.  The Methyl-CpG-binding Protein MeCP2 Links DNA Methylation to Histone Methylation* , 2003, The Journal of Biological Chemistry.

[29]  J. Herman,et al.  GATA-4 and GATA-5 Transcription Factor Genes and Potential Downstream Antitumor Target Genes Are Epigenetically Silenced in Colorectal and Gastric Cancer , 2003, Molecular and Cellular Biology.

[30]  J. Herman,et al.  Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. , 2003, Cancer research.

[31]  Weidong Wang,et al.  Loss of BRG1/BRM in human lung cancer cell lines and primary lung cancers: correlation with poor prognosis. , 2003, Cancer research.

[32]  R. Hruban,et al.  Methylation of cyclin D2 is observed frequently in pancreatic cancer but is also an age-related phenomenon in gastrointestinal tissues. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[33]  R. Jaenisch,et al.  Chromosomal Instability and Tumors Promoted by DNA Hypomethylation , 2003, Science.

[34]  A. Feinberg,et al.  Loss of IGF2 Imprinting: A Potential Marker of Colorectal Cancer Risk , 2003, Science.

[35]  M. Ehrlich The ICF syndrome, a DNA methyltransferase 3B deficiency and immunodeficiency disease. , 2003, Clinical immunology.

[36]  En Li,et al.  Suv 39 h-Mediated Histone H 3 Lysine 9 Methylation Directs DNA Methylation to Major Satellite Repeats at Pericentric Heterochromatin , 2003 .

[37]  B. Horsthemke,et al.  Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma , 1989, Human Genetics.

[38]  Peter A. Jones,et al.  Distinct localization of histone H3 acetylation and H3-K4 methylation to the transcription start sites in the human genome. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[39]  Hing Y Leung,et al.  Upregulation and Nuclear Recruitment of HDAC1 in Hormone Refractory Prostate Cancer , 2004, The Prostate.

[40]  Peter A. Jones,et al.  Epigenetics in human disease and prospects for epigenetic therapy , 2004, Nature.

[41]  Yong Wang,et al.  An evaluation of new criteria for CpG islands in the human genome as gene markers , 2004, Bioinform..

[42]  Xiang-Jiao Yang The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. , 2004, Nucleic acids research.

[43]  Satoshi Tanaka,et al.  Epigenetic Control of Mouse Oct-4 Gene Expression in Embryonic Stem Cells and Trophoblast Stem Cells* , 2004, Journal of Biological Chemistry.

[44]  M. Lohuizen,et al.  Stem Cells and Cancer The Polycomb Connection , 2004, Cell.

[45]  Rudolf Jaenisch,et al.  Reprogramming of a melanoma genome by nuclear transplantation. , 2004, Genes & development.

[46]  Gangning Liang,et al.  Preferential response of cancer cells to zebularine. , 2004, Cancer cell.

[47]  Yang Shi,et al.  Histone Demethylation Mediated by the Nuclear Amine Oxidase Homolog LSD1 , 2004, Cell.

[48]  Lin He,et al.  MicroRNAs: small RNAs with a big role in gene regulation , 2004, Nature reviews genetics.

[49]  M. Fraga,et al.  Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer , 2005, Nature Genetics.

[50]  A. El-Osta,et al.  Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing , 2005, Nature Genetics.

[51]  Peter A. Jones,et al.  A blueprint for a Human Epigenome Project: the AACR Human Epigenome Workshop. , 2005, Cancer research.

[52]  Chang-Zheng Chen,et al.  MicroRNAs as oncogenes and tumor suppressors. , 2005, The New England journal of medicine.

[53]  Lani F. Wu,et al.  Genome-Scale Identification of Nucleosome Positions in S. cerevisiae , 2005, Science.

[54]  Antoine H. F. M. Peters,et al.  LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription , 2005, Nature.

[55]  A. Feinberg,et al.  Loss of Imprinting of Igf2 Alters Intestinal Maturation and Tumorigenesis in Mice , 2005, Science.

[56]  Suk Woo Nam,et al.  Increased expression of histone deacetylase 2 is found in human gastric cancer , 2005, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[57]  D. Reinberg,et al.  Histone variants meet their match , 2005, Nature Reviews Molecular Cell Biology.

[58]  S. Baylin,et al.  DNA methylation and gene silencing in cancer , 2005, Nature Clinical Practice Oncology.

[59]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[60]  C. Peterson,et al.  ATP-dependent chromatin remodeling. , 2005, Current topics in developmental biology.

[61]  H. Horvitz,et al.  MicroRNA expression profiles classify human cancers , 2005, Nature.

[62]  B. Weissman,et al.  Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells. , 2005, Cancer research.

[63]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[64]  Clare Stirzaker,et al.  Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band , 2006, Nature Genetics.

[65]  A. Feinberg,et al.  The epigenetic progenitor origin of human cancer , 2006, Nature Reviews Genetics.

[66]  M. Fraga,et al.  The Polycomb group protein EZH2 directly controls DNA methylation , 2006, Nature.

[67]  Peter A. Jones,et al.  Epigenetic therapy of cancer: past, present and future , 2006, Nature Reviews Drug Discovery.

[68]  S. Baylin,et al.  Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? , 2006, Nature Reviews Cancer.

[69]  B. Kroesen,et al.  The role of microRNAs in normal hematopoiesis and hematopoietic malignancies , 2006, Leukemia.

[70]  Stephan Sauer,et al.  Chromatin signatures of pluripotent cell lines , 2006, Nature Cell Biology.

[71]  Amos Tanay,et al.  Constitutive Nucleosome Depletion and Ordered Factor Assembly at the GRP78 Promoter Revealed by Single Molecule Footprinting , 2006, PLoS genetics.

[72]  Peter A. Jones,et al.  Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. , 2006, Cancer cell.

[73]  Peter A. Jones,et al.  Epigenetic Activation of Tumor Suppressor MicroRNAs in Human Cancer Cells , 2006, Cell cycle.

[74]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[75]  M. Fraga,et al.  Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers. , 2006, Cancer research.

[76]  Thomas A. Milne,et al.  A PHD finger of NURF couples histone H3 lysine 4 trimethylation with chromatin remodelling , 2006, Nature.

[77]  J. Rogers,et al.  DNA methylation profiling of human chromosomes 6, 20 and 22 , 2006, Nature Genetics.

[78]  R. Paro,et al.  Polycomb/Trithorax response elements and epigenetic memory of cell identity , 2007, Development.

[79]  George P Cobb,et al.  microRNAs as oncogenes and tumor suppressors. , 2007, Developmental biology.

[80]  M. Fraga,et al.  The Polycomb group protein EZH2 directly controls DNA methylation , 2007, Nature.

[81]  T. Kouzarides Chromatin Modifications and Their Function , 2007, Cell.

[82]  Yang Shi,et al.  Histone lysine demethylases: emerging roles in development, physiology and disease , 2007, Nature Reviews Genetics.

[83]  T. Mikkelsen,et al.  Genome-wide maps of chromatin state in pluripotent and lineage-committed cells , 2007, Nature.

[84]  E. Lander,et al.  The Mammalian Epigenome , 2007, Cell.

[85]  Zohar Yakhini,et al.  Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer , 2007, Nature Genetics.

[86]  P. Molloy,et al.  DNA hypomethylation and human diseases. , 2007, Biochimica et biophysica acta.

[87]  C. Jin,et al.  Nucleosome stability mediated by histone variants H3.3 and H2A.Z. , 2007, Genes & development.

[88]  Xinmin Zhou,et al.  Promoter Hypermethylation of the RUNX3 Gene in Esophageal Squamous Cell Carcinoma , 2007, Cancer investigation.

[89]  Hideaki Kato,et al.  Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas , 2007, Hepatology research : the official journal of the Japan Society of Hepatology.

[90]  C. Jin,et al.  Nucleosome stability mediated by histone variants H 3 . 3 and H 2 , 2007 .

[91]  P. Laird,et al.  Epigenetic stem cell signature in cancer , 2007, Nature Genetics.

[92]  Peter A. Jones,et al.  Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. , 2007, Cancer cell.

[93]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[94]  E. Plimack,et al.  Decitabine and its role in the treatment of hematopoietic malignancies , 2007, Leukemia & lymphoma.

[95]  M. Surani,et al.  Genetic and Epigenetic Regulators of Pluripotency , 2007, Cell.

[96]  Scott A. Armstrong,et al.  MLL translocations, histone modifications and leukaemia stem-cell development , 2007, Nature Reviews Cancer.

[97]  Kelly M. McGarvey,et al.  A stem cell–like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing , 2007, Nature Genetics.

[98]  Qiang Yu,et al.  Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. , 2007, Genes & development.

[99]  J. Serth,et al.  Adiposity and Age are Statistically Related to Enhanced RASSF1A Tumor Suppressor Gene Promoter Methylation in Normal Autopsy Kidney Tissue , 2007, Cancer Epidemiology Biomarkers & Prevention.

[100]  C. Morrison,et al.  MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B , 2007, Proceedings of the National Academy of Sciences.

[101]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[102]  S. Henikoff,et al.  Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks , 2008, Nature.

[103]  Bryan J Venters,et al.  A barrier nucleosome model for statistical positioning of nucleosomes throughout the yeast genome. , 2008, Genome research.

[104]  Francis J Giles,et al.  Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. , 2008, Cancer letters.

[105]  J. Issa,et al.  Downregulation of Histone H3 Lysine 9 Methyltransferase G9a Induces Centrosome Disruption and Chromosome Instability in Cancer Cells , 2008, PloS one.

[106]  Peter A. Jones,et al.  Chromatin, cancer and drug therapies. , 2008, Mutation research.

[107]  H. Kimura,et al.  G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription , 2008, The EMBO journal.

[108]  Jordanka Zlatanova,et al.  H2A.Z: view from the top. , 2008, Structure.

[109]  Dustin E. Schones,et al.  Dynamic Regulation of Nucleosome Positioning in the Human Genome , 2008, Cell.

[110]  S. Minucci,et al.  MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks , 2008, Molecular and Cellular Biology.

[111]  S. Ropero,et al.  A microRNA DNA methylation signature for human cancer metastasis , 2008, Proceedings of the National Academy of Sciences.

[112]  Jim Stalker,et al.  A Novel CpG Island Set Identifies Tissue-Specific Methylation at Developmental Gene Loci , 2008, PLoS biology.

[113]  R. Jaenisch,et al.  Activation and transposition of endogenous retroviral elements in hypomethylation induced tumors in mice , 2008, Oncogene.

[114]  R. Young,et al.  H2AZ Is Enriched at Polycomb Complex Target Genes in ES Cells and Is Necessary for Lineage Commitment , 2008, Cell.

[115]  Michael Q. Zhang,et al.  Combinatorial patterns of histone acetylations and methylations in the human genome , 2008, Nature Genetics.

[116]  Michel C Nussenzweig,et al.  MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. , 2008, Immunity.

[117]  George Coukos,et al.  Mechanisms of microRNA deregulation in human cancer , 2008, Cell cycle.

[118]  Steven J. M. Jones,et al.  Dynamic Remodeling of Individual Nucleosomes Across a Eukaryotic Genome in Response to Transcriptional Perturbation , 2007, PLoS biology.

[119]  Gangning Liang,et al.  Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line , 2008, Proceedings of the National Academy of Sciences.

[120]  A. Bird,et al.  DNA methylation landscapes: provocative insights from epigenomics , 2008, Nature Reviews Genetics.

[121]  K. Helin,et al.  Erasing the methyl mark: histone demethylases at the center of cellular differentiation and disease. , 2008, Genes & development.

[122]  J. Mendell miRiad Roles for the miR-17-92 Cluster in Development and Disease , 2008, Cell.

[123]  M. Toyota,et al.  Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer. , 2008, Cancer research.

[124]  H. Cedar,et al.  Linking DNA methylation and histone modification: patterns and paradigms , 2009, Nature Reviews Genetics.

[125]  Cizhong Jiang,et al.  Nucleosome positioning and gene regulation: advances through genomics , 2009, Nature Reviews Genetics.

[126]  R. Versteeg,et al.  Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy. , 2009, Cancer research.

[127]  K. Ghoshal,et al.  A new class of quinoline-based DNA hypomethylating agents reactivates tumor suppressor genes by blocking DNA methyltransferase 1 activity and inducing its degradation. , 2009, Cancer research.

[128]  Andrea Ventura,et al.  MicroRNAs and Cancer: Short RNAs Go a Long Way , 2009, Cell.

[129]  E. Li,et al.  The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation , 2009, Nature Genetics.

[130]  B. Emerson,et al.  Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary. , 2009, Molecular cell.

[131]  N. Gevry,et al.  Regulation of gene expression and cellular proliferation by histone H2A.Z. , 2009, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[132]  S. Jacobsen,et al.  Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells , 2009, Proceedings of the National Academy of Sciences.

[133]  Peter A. Jones,et al.  The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the polycomb group protein EZH2. , 2009, Cancer research.

[134]  D. Reisman,et al.  The SWI/SNF complex and cancer , 2009, Oncogene.

[135]  M. Torres-Padilla,et al.  Epigenetic reprogramming in mammalian reproduction: Contribution from histone variants , 2009, Epigenetics.

[136]  A. Schnerch,et al.  Characterization of human embryonic stem cells with features of neoplastic progression , 2009, Nature Biotechnology.

[137]  Robert L Moritz,et al.  PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing , 2009, Nature Structural &Molecular Biology.

[138]  E. Androphy,et al.  The SWI/SNF chromatin remodeling subunit BRG1 is a critical regulator of p53 necessary for proliferation of malignant cells , 2009, Oncogene.

[139]  E. Olson,et al.  The many roles of histone deacetylases in development and physiology: implications for disease and therapy , 2009, Nature Reviews Genetics.

[140]  Peter A. Jones,et al.  DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation , 2009, Molecular Cancer Therapeutics.

[141]  A. Feinberg,et al.  Large histone H3 lysine 9 dimethylated chromatin blocks distinguish differentiated from embryonic stem cells , 2009, Nature Genetics.