DNA methylation and gene silencing in cancer: which is the guilty party?

The DNA methylation pattern of a cell is exquisitely controlled during early development resulting in distinct methylation patterns. The tight control of DNA methylation is released in the cancer cell characterized by a reversal of methylation states. CpG island associated genes, in particular tumour suppressor or related genes, are often hypermethylated and this is associated with silencing of these genes. Therefore methylation is commonly convicted as a critical causal event in silencing this important class of genes in cancer. In this review, we argue that methylation is not the initial guilty party in triggering gene silencing in cancer, but that methylation of CpG islands is a consequence of prior gene silencing, similar to the role of methylation in maintaining the silencing of CpG island genes on the inactive X chromosome. We propose that gene silencing is the critical precursor in cancer, as it changes the dynamic interplay between de novo methylation and demethylation of the CpG island and tilts the balance to favour hypermethylation and chromatin inactivation.

[1]  S. Baylin,et al.  Increased cytosine DNA-methyltransferase activity is target-cell-specific and an early event in lung cancer. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

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

[3]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[4]  H. J. Evans,et al.  Advances in Cancer Research , 1985, British Journal of Cancer.

[5]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[6]  Z. Siegfried,et al.  Spl elements protect a CpG island from de novo methylation , 1994, Nature.

[7]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[8]  C. Walsh,et al.  Cytosine methylation and the ecology of intragenomic parasites. , 1997, Trends in genetics : TIG.

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

[10]  S. Clark,et al.  Hypermethylation trigger of the glutathione-S-transferase gene (GSTP1) in prostate cancer cells , 2002, Oncogene.

[11]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[12]  S. Clark,et al.  DNA Methylation Profile of the Mouse Skeletal α-Actin Promoter during Development and Differentiation , 1999, Molecular and Cellular Biology.

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

[14]  P. Jones,et al.  The DNA methylation paradox. , 1999, Trends in genetics : TIG.

[15]  S. Iguchi-Ariga,et al.  CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. , 1989, Genes & development.

[16]  N. Tommerup,et al.  Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene , 1999, Nature.

[17]  F. Watt,et al.  DNA methylation and specific protein-DNA interactions. , 1990, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[18]  A. Feinberg,et al.  Limited up-regulation of DNA methyltransferase in human colon cancer reflecting increased cell proliferation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[19]  Rudolf Jaenisch,et al.  Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X Chromosome Inactivation , 2001, The Journal of cell biology.

[20]  M. Gammage.  Pacing approaches to the patient with a univentricular heart and the factors associated with choice of pacing site. , 2000, Pacing and clinical electrophysiology : PACE.

[21]  N. Brockdorff,et al.  Histone H3 Lysine 9 Methylation Occurs Rapidly at the Onset of Random X Chromosome Inactivation , 2002, Current Biology.

[22]  S. Clark,et al.  Bisulfite sequencing in preimplantation embryos: DNA methylation profile of the upstream region of the mouse imprinted H19 gene. , 1998, Genomics.

[23]  J. Walter,et al.  Embryogenesis: Demethylation of the zygotic paternal genome , 2000, Nature.

[24]  T. Fanning,et al.  Differential methylation of human LINE-1 retrotransposons in malignant cells. , 1996, Gene.

[25]  R. Beart,et al.  Mechanisms for the involvement of DNA methylation in colon carcinogenesis. , 1996, Cancer research.

[26]  M. Szyf,et al.  Demethylase Activity Is Directed by Histone Acetylation* , 2001, The Journal of Biological Chemistry.

[27]  S. Clark,et al.  Detailed methylation analysis of the glutathione S-transferase π (GSTP1) gene in prostate cancer , 1999, Oncogene.

[28]  A. Bird,et al.  Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island. , 1994, Genes & development.

[29]  Thierry Boon,et al.  DNA Methylation Is the Primary Silencing Mechanism for a Set of Germ Line- and Tumor-Specific Genes with a CpG-Rich Promoter , 1999, Molecular and Cellular Biology.

[30]  J. Herman,et al.  p15(INK4B) CpG island methylation in primary acute leukemia is heterogeneous and suggests density as a critical factor for transcriptional silencing. , 1999, Blood.

[31]  J. Herman,et al.  DNA hypermethylation in tumorigenesis: epigenetics joins genetics. , 2000, Trends in genetics : TIG.

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

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

[34]  P. Warnecke,et al.  Increased DNA methyltransferase expression in leukaemia , 1998, Leukemia.

[35]  Benjamin Tycko,et al.  Creation of genomic methylation patterns , 1996, Nature Genetics.

[36]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[37]  M. Frommer,et al.  CpG islands in vertebrate genomes. , 1987, Journal of molecular biology.

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

[39]  S. Clark,et al.  Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. , 1999, Cancer research.

[40]  K. Akashi,et al.  Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. , 2001, Blood.

[41]  M. Monk.  Changes in DNA methylation during mouse embryonic development in relation to X-chromosome activity and imprinting. , 1990, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[42]  A. Bird,et al.  Number of CpG islands and genes in human and mouse. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Robert L. Tanguay,et al.  In vivo footprint and methylation analysis by PCR-aided genomic sequencing: comparison of active and inactive X chromosomal DNA at the CpG island and promoter of human PGK-1. , 1990, Genes & development.

[44]  J. Herman,et al.  Expression of an exogenous eukaryotic DNA methyltransferase gene induces transformation of NIH 3T3 cells. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Brooks,et al.  Cytidine methylation of regulatory sequences near the pi-class glutathione S-transferase gene accompanies human prostatic carcinogenesis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[46]  Hypermethylation of E-cadherin in leukemia. , 2000 .

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

[48]  M. Siegmann,et al.  The RNA moiety of chick embryo 5-methylcytosine- DNA glycosylase targets DNA demethylation. , 1997, Nucleic acids research.

[49]  K. Robertson,et al.  The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. , 1999, Nucleic acids research.

[50]  S. Baylin,et al.  Increased cytosine DNA-methyltransferase activity during colon cancer progression. , 1993, Journal of the National Cancer Institute.

[51]  A. Wolffe,et al.  How does DNA methylation repress transcription? , 1997, Trends in genetics : TIG.

[52]  E. Li,et al.  Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases , 1998, Nature Genetics.

[53]  S. Clark,et al.  A Distinct Sequence (ATAAA) n Separates Methylated and Unmethylated Domains at the 5′-End of theGSTP1 CpG Island*210 , 2000, The Journal of Biological Chemistry.

[54]  V. Ingram,et al.  Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. , 1988, Journal of molecular biology.

[55]  R. Weinberg,et al.  Suppression of intestinal neoplasia by DNA hypomethylation , 1995, Cell.

[56]  Huidong Shi,et al.  Methylation-specific oligonucleotide microarray: a new potential for high-throughput methylation analysis. , 2002, Genome research.

[57]  F. Soussaline,et al.  A CpG-rich RNA and an RNA helicase tightly associated with the DNA demethylation complex are present mainly in dividing chick embryo cells. , 2000, European journal of cell biology.

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

[59]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

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

[61]  R. E. Thayer,et al.  Undermethylation of specific LINE-1 sequences in human cells producing a LINE-1-encoded protein. , 1993, Gene.

[62]  I. Pogribny,et al.  Alterations in hepatic p53 gene methylation patterns during tumor progression with folate/methyl deficiency in the rat. , 1997, Cancer letters.