Cancer epigenetics: above and beyond

Epigenetics refers to the study of mechanisms that alter gene expression without altering the primary DNA sequence. Epigenetic mechanisms are heritable and reversible. Over the last few decades, epigenetics has obtained a large importance in cancer research. Epigenetic alterations are widely described as essential players in cancer progression. They comprise DNA methylation, histone modifications, nucleosome positioning, and small, noncoding RNAs (miRNA, siRNA). They are involved in transcriptional changes and decisive events that will determine cell fate and phenotype. Epigenetics not only offers light into cancer biological processes, but also represents an attractive opportunity of reverting cancer-specific alterations, which may lead, in the future, to a possibility of stopping this disease. Epigenetic changes have been identified as putative cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. Other epigenetic alterations are promising therapeutic targets and even therapeutic agents. Emerging discoveries in this area are already contributing to cancer management and monitoring, and a lot more progresses are expected in the future.

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

[2]  Hong Peng,et al.  Altered miRNA expression in sputum for diagnosis of non-small cell lung cancer. , 2010, Lung cancer.

[3]  Peter A. Jones,et al.  Cellular differentiation, cytidine analogs and DNA methylation , 1980, Cell.

[4]  R C Coombes,et al.  Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

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

[6]  R. Feil,et al.  Chromatin mechanisms in genomic imprinting , 2009, Mammalian Genome.

[7]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

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

[9]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[10]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[11]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[12]  P. Laird Cancer epigenetics. , 2005, Human molecular genetics.

[13]  Peter A. Jones,et al.  Hypomethylation of a LINE-1 Promoter Activates an Alternate Transcript of the MET Oncogene in Bladders with Cancer , 2010, PLoS genetics.

[14]  Daniel B. Martin,et al.  Circulating microRNAs as stable blood-based markers for cancer detection , 2008, Proceedings of the National Academy of Sciences.

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

[16]  A. Partin,et al.  p300 (histone acetyltransferase) biomarker predicts prostate cancer biochemical recurrence and correlates with changes in epithelia nuclear size and shape , 2008, The Prostate.

[17]  S. Henikoff,et al.  Genome-wide analysis of Arabidopsis thaliana DNA methylation uncovers an interdependence between methylation and transcription , 2007, Nature Genetics.

[18]  Ruian Xu,et al.  Potential uses of microRNA in lung cancer diagnosis, prognosis, and therapy. , 2009, Current cancer drug targets.

[19]  Ping Zhu,et al.  Induction of HDAC2 expression upon loss of APC in colorectal tumorigenesis. , 2004, Cancer cell.

[20]  Illinois.,et al.  Cancer Genetics , 1976, British Journal of Cancer.

[21]  Robert S. Illingworth,et al.  CpG islands influence chromatin structure via the CpG-binding protein Cfp1 , 2010, Nature.

[22]  A. Knudson Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

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

[24]  S. C. Lakhotia,et al.  What is a gene? , 1997 .

[25]  David I. K. Martin,et al.  Epigenetic inheritance at the agouti locus in the mouse , 1999, Nature Genetics.

[26]  K. Kelnar,et al.  The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. , 2011, Nature medicine.

[27]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[28]  Paul Cairns,et al.  Gene methylation and early detection of genitourinary cancer: the road ahead , 2007, Nature Reviews Cancer.

[29]  M. Esteller Epigenetic gene silencing in cancer: the DNA hypermethylome. , 2007, Human molecular genetics.

[30]  G. Riddihough,et al.  What Is Epigenetics , 2010 .

[31]  M. Surani,et al.  Epigenetic reprogramming in mouse primordial germ cells , 2002, Mechanisms of Development.

[32]  Manel Esteller,et al.  How epigenetics integrates nuclear functions , 2005 .

[33]  A. Bird,et al.  Genomic DNA methylation: the mark and its mediators. , 2006, Trends in biochemical sciences.

[34]  B. Weissman,et al.  Hijacking the chromatin remodeling machinery: impact of SWI/SNF perturbations in cancer. , 2009, Cancer research.

[35]  W. Reik,et al.  Epigenetic Reprogramming in Mammalian Development , 2001, Science.

[36]  Fabricio F Costa,et al.  Cancer Management and Research Dovepress Epigenomics in Cancer Management , 2022 .

[37]  David Sidransky,et al.  MicroRNA alterations in head and neck squamous cell carcinoma , 2008, International journal of cancer.

[38]  Reuven Agami,et al.  Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. , 2007, The EMBO journal.

[39]  R. Weinberg,et al.  Micromanagers of malignancy: role of microRNAs in regulating metastasis. , 2008, Trends in genetics : TIG.

[40]  M. Surani,et al.  Genomic imprinting and cancer. , 1995, Cancer surveys.

[41]  Kelly M. McGarvey,et al.  The cancer epigenome--components and functional correlates. , 2006, Genes & development.

[42]  L. Looijenga,et al.  Testicular germ-cell tumours in a broader perspective , 2005, Nature Reviews Cancer.

[43]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Steven S. Chang,et al.  Integrative Discovery of Epigenetically Derepressed Cancer Testis Antigens in NSCLC , 2009, PloS one.

[45]  David Sidransky,et al.  Emerging molecular markers of cancer , 2002, Nature Reviews Cancer.

[46]  S. Minucci,et al.  Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer , 2006, Nature Reviews Cancer.

[47]  Y. Yatabe,et al.  A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. , 2005, Cancer research.

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

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

[50]  A. Lal,et al.  MicroRNAs and their target gene networks in breast cancer , 2010, Breast Cancer Research.

[51]  C. Croce,et al.  MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. , 2007, Endocrine-related cancer.

[52]  A. Sparreboom,et al.  Rational Development of Histone Deacetylase Inhibitors as Anticancer Agents: A Review , 2005, Molecular Pharmacology.

[53]  J. Issa CpG island methylator phenotype in cancer , 2004, Nature Reviews Cancer.

[54]  F. Costa,et al.  Non‐coding RNAs: Meet thy masters , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[55]  J. Jost,et al.  The formation of DNA methylation patterns and the silencing of genes. , 1997, Progress in nucleic acid research and molecular biology.

[56]  Z. Herceg,et al.  Epigenetic drivers and genetic passengers on the road to cancer. , 2008, Mutation research.

[57]  H. Sültmann,et al.  The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. , 2007, Cancer research.

[58]  Hengbin Wang,et al.  Role of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing , 2002, Science.

[59]  S. Zukin,et al.  Epigenetics , 2009, Alzheimer's & Dementia.

[60]  M. Esteller,et al.  Proteins that bind methylated DNA and human cancer: reading the wrong words , 2008, British Journal of Cancer.

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

[62]  L. Aaltonen,et al.  A truncating mutation of HDAC2 in human cancers confers resistance to histone deacetylase inhibition , 2006, Nature Genetics.

[63]  D. Pisano,et al.  Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs , 2008, Cell cycle.

[64]  M. Ehrlich DNA hypomethylation, cancer, the immunodeficiency, centromeric region instability, facial anomalies syndrome and chromosomal rearrangements. , 2002, Journal of NutriLife.

[65]  E. Schuuring,et al.  Genome-wide promoter analysis uncovers portions of the cancer methylome. , 2008, Cancer research.

[66]  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.

[67]  P. V. van Helden,et al.  Hypomethylation of DNA in pathological conditions of the human prostate. , 1987, Cancer research.

[68]  Peter A. Jones,et al.  Cancer epigenetics: modifications, screening, and therapy. , 2008, Annual review of medicine.

[69]  Adrian Bird,et al.  The essentials of DNA methylation , 1992, Cell.

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

[71]  M. Caligiuri,et al.  Aberrant CpG-island methylation has non-random and tumour-type–specific patterns , 2000, Nature Genetics.

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

[73]  Carla Oliveira,et al.  A TARBP2 mutation in human cancer impairs microRNA processing and DICER1 function , 2009, Nature Genetics.

[74]  F. Costa,et al.  The impact of microRNAs and alternative splicing in pharmacogenomics , 2009, The Pharmacogenomics Journal.

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

[76]  J. Hicks,et al.  Global DNA hypomethylation in intratubular germ cell neoplasia and seminoma, but not in nonseminomatous male germ cell tumors , 2008, Modern Pathology.

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

[78]  Jingde Zhu,et al.  Use of DNA methylation for cancer detection: promises and challenges. , 2009, The international journal of biochemistry & cell biology.

[79]  C. Allis,et al.  Covalent histone modifications — miswritten, misinterpreted and mis-erased in human cancers , 2010, Nature Reviews Cancer.

[80]  Arthur D. Riggs,et al.  X inactivation, differentiation, and DNA methylation. , 1975, Cytogenetics and cell genetics.

[81]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[82]  Rachel Jones,et al.  Behavioural genetics: Worms gang up on bacteria , 2002, Nature Reviews Genetics.

[83]  Israel Steinfeld,et al.  Developmental programming of CpG island methylation profiles in the human genome , 2009, Nature Structural &Molecular Biology.

[84]  Manoj Bhasin,et al.  Recognition and Classification of Histones Using Support Vector Machine , 2006, J. Comput. Biol..

[85]  Hsien-Da Huang,et al.  MicroRNA‐122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma , 2009, Hepatology.

[86]  R. Agami,et al.  Tumorigenicity of the miR-17-92 cluster distilled. , 2010, Genes & development.

[87]  Steven S. Chang,et al.  Coordinated Activation of Candidate Proto-Oncogenes and Cancer Testes Antigens via Promoter Demethylation in Head and Neck Cancer and Lung Cancer , 2009, PloS one.

[88]  D. Bartel,et al.  The impact of microRNAs on protein output , 2008, Nature.

[89]  M. Hoque,et al.  Epigenomics and ovarian carcinoma. , 2010, Biomarkers in medicine.

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

[91]  G. Längst,et al.  Nucleosome remodeling: one mechanism, many phenomena? , 2004, Biochimica et biophysica acta.

[92]  Cyrus Martin,et al.  The diverse functions of histone lysine methylation , 2005, Nature Reviews Molecular Cell Biology.

[93]  A. Chess,et al.  Gene Body-Specific Methylation on the Active X Chromosome , 2007, Science.

[94]  M. Esteller,et al.  Epigenetic modifications and human disease , 2010, Nature Biotechnology.

[95]  D. Ghosh,et al.  A polycomb repression signature in metastatic prostate cancer predicts cancer outcome. , 2007, Cancer research.

[96]  Dieter Jocham,et al.  A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer. , 2010, Urologic oncology.

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

[98]  C. Croce,et al.  miR-15 and miR-16 induce apoptosis by targeting BCL2. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[99]  P. Laird,et al.  Hypomethylation and hypermethylation of DNA in Wilms tumors , 2002, Oncogene.

[100]  Reuven Agami,et al.  Regulation of the p27Kip1 tumor suppressor by miR‐221 and miR‐222 promotes cancer cell proliferation , 2007 .

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

[102]  T. Bestor,et al.  Formation of methylation patterns in the mammalian genome. , 1997, Mutation research.

[103]  S. Baylin,et al.  Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genes , 2007, Proceedings of the National Academy of Sciences.

[104]  P. Georgel,et al.  Linker histone function in chromatin: dual mechanisms of action. , 2001, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[105]  J. Califano,et al.  DNA global hypomethylation in squamous cell head and neck cancer associated with smoking, alcohol consumption and stage , 2007, International journal of cancer.

[106]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[107]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

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

[109]  Irene K. Moore,et al.  A genomic code for nucleosome positioning , 2006, Nature.

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

[111]  Ricky W. Johnstone,et al.  Histone-deacetylase inhibitors: novel drugs for the treatment of cancer , 2002, Nature Reviews Drug Discovery.

[112]  Sun-Mi Park,et al.  The role of let-7 in cell differentiation and cancer. , 2010, Endocrine-related cancer.

[113]  J. Issa,et al.  DNA Methylation as a Therapeutic Target in Cancer , 2007, Clinical Cancer Research.

[114]  Carolyn J. Brown,et al.  Epigenetics of cancer progression. , 2008, Pharmacogenomics.

[115]  司履生 Cancer epigenetics , 2006 .

[116]  J. Issa DNA methylation as a therapeutic target in cancer. , 2008, Clinical cancer research : an official journal of the American Association for Cancer Research.

[117]  M. Hoque DNA methylation changes in prostate cancer: current developments and future clinical implementation , 2009, Expert review of molecular diagnostics.

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

[119]  B. Czerniak,et al.  Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

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

[121]  B. Cairns,et al.  The biology of chromatin remodeling complexes. , 2009, Annual review of biochemistry.

[122]  J. Herman,et al.  Specific Inhibition of DNMT1 by Antisense Oligonucleotides Induces Re-expression of Estrogen Receptor a (ER) in ER-negative Human Breast Cancer Cell Lines , 2003, Cancer biology & therapy.

[123]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[124]  Peter A. Jones,et al.  Epigenetics in cancer. , 2010, Carcinogenesis.

[125]  C. Scrideli,et al.  Differential expression of 12 histone deacetylase (HDAC) genes in astrocytomas and normal brain tissue: class II and IV are hypoexpressed in glioblastomas , 2008, BMC Cancer.

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

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

[128]  J. Licht,et al.  Deregulation of H3K27 methylation in cancer , 2010, Nature Genetics.

[129]  M. Surani,et al.  Cancer genetics. Genomic imprinting and embryonal tumours. , 1989, Nature.

[130]  J. Herman,et al.  Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. , 2000, Cancer research.

[131]  K. Struhl Histone acetylation and transcriptional regulatory mechanisms. , 1998, Genes & development.

[132]  Anna M. Krichevsky,et al.  miR-21: a small multi-faceted RNA , 2008, Journal of cellular and molecular medicine.

[133]  Debashis Ghosh,et al.  EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

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

[135]  Y. Fujii,et al.  Regulation of human immunodeficiency virus 1 transcription by nef microRNA. , 2005, The Journal of general virology.

[136]  A. M. Salazar,et al.  Reactivation of tumor suppressor genes by the cardiovascular drugs hydralazine and procainamide and their potential use in cancer therapy. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[137]  R. Bast,et al.  The Roles of MicroRNAs in the Cancer Invasion-Metastasis Cascade , 2010, Cancer Microenvironment.

[138]  T. Wurdinger,et al.  Molecular therapy in the microRNA era , 2007, The Pharmacogenomics Journal.

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

[140]  W. Filipowicz,et al.  Inhibition of Translational Initiation by Let-7 MicroRNA in Human Cells , 2005, Science.

[141]  J. Yoshida,et al.  Epigenetic aberrations and therapeutic implications in gliomas , 2010, Cancer science.

[142]  E. Eisenhauer,et al.  DNA methyltransferase inhibitors-state of the art. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[143]  Lloyd J. Old,et al.  Cancer/testis antigens, gametogenesis and cancer , 2005, Nature Reviews Cancer.

[144]  Yue-hua Ma,et al.  New clinical developments in histone deacetylase inhibitors for epigenetic therapy of cancer , 2009, Journal of hematology & oncology.

[145]  David Sidransky,et al.  DNA methylation markers in colorectal cancer , 2010, Cancer and Metastasis Reviews.

[146]  M. Surani,et al.  Genomic imprinting and embryonal tumours , 1989, Nature.

[147]  Cizhong Jiang,et al.  A compiled and systematic reference map of nucleosome positions across the Saccharomyces cerevisiae genome , 2009, Genome Biology.

[148]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[149]  Helmut Gernsheim,et al.  W. H. Fox Talbot and the history of photography , 1977 .

[150]  J. Herman,et al.  5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers , 1995, Nature Medicine.