Abstract
The recognition of epigenetic defects in all types of cancer has represented a revolutionary achievement in cancer research in recent years. DNA methylation aberrant changes (global hypomethylation and CpG island hypermethylation) were among the first events to be recognized. The overall scenario comprises a network of factors in which deregulation of DNA methyltransferases leads to a cancer-type specific profile of tumor suppressor genes that become epigenetically silenced. Over recent years, a better understanding of the machinery that connects DNA methylation, chromatin and transcriptional activity, in which histone modifications stand in a key position, has been achieved. The identification of these connections has contributed not only to understanding how epigenetic deregulation occurs in cancer but also to developing novel therapies that can reverse epigenetic defects in cancer cells.
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References
Allfrey V, Faulkner RM, Mirsky AE (1964) Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc Natl Acad Sci USA 51:786–794
Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW, Vogelstein B (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3:89–95
Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada, J, Cigudosa JC, Huang TH-M, Esteller M (2003) Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J 22:1–11
Bestor TH, Laudano A, Mattaliano R, Ingram V (1988) Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzyme is related to bacterial restriction methyltransferases. J Mol Biol 203:971–983
Bird A (1992) The essentials of DNA methylation. Cell 70:5–8
Cedar H (1988) DNA methylation and gene activity. Cell 53:3–4
Chen T, Ueda Y, Dodge JE, Wang Z, Li E (2003) Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol Cell Biol 23:5594–5605
Costello JF, Smiraglia DJ, Plass C (2002) Restriction landmark genome scanning. Methods 27:144–149
Daniel JM, Reynolds AB (1999) The catenin p120(ctn) interacts with Kaiso, a novel BTB/POZ domain zinc finger transcription factor. Mol Cell Biol 19:3614–3623
Deng G, Chen A, Pong E, Kim YS (2001) Methylation in hMLH1 promoter interferes with its binding to transcription factor CBF and inhibits gene expression. Oncogene 20:7120–7127
Di Croce L, Raker VA, Corsaro M, Fazi F, Fanelli M, Faretta M, Fuks F, Lo Coco F, Kouzarides T, Nervi C, Minucci S, Pelicci PG (2002) Methyltransferase recruitment and DNA hyper-methylation of target promoters by an oncogenic transcription factor. Science 295:1079–1082
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440
Esteller M, Corn PG, Baylin SB, Herman JG (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3229
Esteller M, Fraga MF, Paz MF, Campo E, Colomer D, Novo FJ, Calasanz MJ, Galm O, Guo M, Benitez J, Herman JG (2002) Cancer epigenetics and methylation. Science 297:1807–1808
Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M (2003) Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J Biol Chem 278:24132–24138
Fuks F, Burgers WA, Godin N, Kasai M, Kouzarides T (2001) Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription. EMBO J 20:2536–2544
Fuks F, Hurd PJ, Deplus R, Kouzarides T (2003a) The DNA methyltransferases associate with HP1 and the SUV39H1 histone methyltransferase. Nucleic Acids Res 31:2305–2312
Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP, Kouzarides T (2003b) The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation. J Biol Chem 278:4035–4040
Hendrich B, Bird AP (1998) Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol 18:6538–6547
Herman JG, Latif F, Weng Y, Lerman MI, Zbar B, Liu S, Samid D, Duan DS, Gnarra JR, Linehan WM, Baylin SB (1994) Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci USA 91:9700–9704
Hermann A, Schmitt S, Jeltsch A (2003) The human Dnmt2 has residual DNA-(cytosine-C5) methyltransferase activity. J Biol Chem 278:31717–31721
Jamieson AC, Miller JC, Pabo CO (2003) Drug discovery with engineered zinc-finger proteins. Nat Rev Drug Discov 2:361–368
Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J, Wolffe AP (1998) Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet 19:187–191
Kass SU, Pruss D, Wolffe AP (1997) How does DNA methylation repress transcription? Trends Genet 13:444–449
Keshet I, Lieman-Hurwitz J, Cedar H (1986) DNA methylation affects the formation of active chromatin. Cell 44:535–545
Kim GD, Ni J, Kelesoglu N, Roberts RJ, Pradhan S (2002) Co-operation and communication between the human maintenance and de novo DNA (cytosine-5) methyltransferases. EMBO J 21:4183–4195
Lee JH, Skalnik DG (2002) CpG-binding protein is a nuclear matrix-and euchromatin-associated protein localized to nuclear speckles containing human trithorax. Identification of nuclear matrix targeting signals. J Biol Chem 277:42259–42267
Lee JH, Voo KS, Skalnik DG (2001) Identification and characterization of the DNA binding domain of CpG-binding protein. J Biol Chem 276:44669–44676
Lewis JD, Meehan RR, Henzel WJ, Maurer-Fogy I, Jeppesen P, Klein F, Bird A (1992) Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69:905–914
Magdinier F, Wolffe AP (2001) Selective association of the methyl-CpG binding protein MBD2 with the silent p14/p16 locus in human neoplasia. Proc Natl Acad Sci USA 98:4990–4995
Meehan RR, Lewis JD, Bird AP (1992) Characterization of MeCP2, a vertebrate DNA binding protein with affinity for methylated DNA. Nucleic Acids Res 20:5085–5092
Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN, Bird A (1998) Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393:386–389
Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D, Bird A (1999) MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet 23:58–61
Ng HH, Jeppesen P, Bird A (2000) Active repression of methylated genes by the chromosomal protein MBD1. Mol Cell Biol 20:1394–1406
Nguyen CT, Gonzales FA, Jones PA (2001) Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic Acids Res 29:4598–4606
Okano M, Xie S, Li E (1998) Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat Genet 19:219–220
Okano M, Bell DW, Haber DA, Li E (1999) DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257
Paz MF, Fraga MF, Avila S, Guo M, Pollan M, Herman JG, Esteller M (2003a) A systematic profile of DNA methylation in human cancer cell lines. Cancer Res 63:1114–1121
Paz MF, Wei S, Cigudosa JC, Rodriguez-Perales S, Peinado MA, Huang TH, Esteller M (2003b) Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases. Hum Mol Genet 12:2209–2219
Prokhortchouk A, Hendrich B, Jorgensen H, Ruzov A, Wilm M, Georgiev G, Bird A, Prokhortchouk E (2001) The p120 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor. Genes Dev 15:1613–1618
Rhee I, Jair KW, Yen RW, Lengauer C, Herman JG, Kinzler KW, Vogelstein B, Baylin SB, Schuebel KE (2000) CpG methylation is maintained in human cancer cells lacking DNMT1. Nature 404:1003–1007
Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL, Wolffe AP (2000) DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters. Nat Genet 25:338–342
Snowden AW, Zhang L, Urnov F, Dent C, Jouvenot Y, Zhong X, Rebar EJ, Jamieson AC, Zhang HS, Tan S, Case CC, Pabo CO, Wolffe AP, Gregory PD (2003) Repression of vascular endothelial growth factor A in glioblastoma cells using engineered zinc finger transcription factors. Cancer Res 63:8968–8976
Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45
Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31:141–149
Tate PH, Bird AP (1993) Effects of DNA methylation on DNA-binding proteins and gene expression. Curr Opin Genet Dev 3:226–231
Turner BM (2002) Cellular memory and the histone code. Cell 111:285–291
Villar-Garea A, Esteller M (2003) DNA demethylating agents and chromatin-remodelling drugs: which, how and why? Curr Drug Metab 4:11–31
Villar-Garea A, Fraga MF, Espada J, Esteller M (2003) Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res 63:4984–4989
Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F, Wolffe AP (1999) Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation. Nat Genet 23:62–66
Yoder JA, Walsh CP, Bestor TH (1997) Cytosine methylation and the ecology of intragenomic parasites. Trends Genet 13:335–340
Yoder JA, Bestor TH (1998) A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284
Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (2003) N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell 12:723–734
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Ballestar, E., Esteller, M. (2005). The Epigenetic Breakdown of Cancer Cells: From DNA Methylation to Histone Modifications. In: Jeanteur, P. (eds) Epigenetics and Chromatin. Progress in Molecular and Subcellular Biology, vol 38. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27310-7_7
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DOI: https://doi.org/10.1007/3-540-27310-7_7
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