Abstract
The discovery that drastic changes in DNA methylation and histone modifications are common in human tumors has inspired various laboratories and pharmaceutical companies to develop and study epigenetic drugs. One of the most promising groups of agents is the inhibitors of histone deacetylases (HDACs), which have different biochemical and biologic properties but have a single common activity: induction of acetylation in histones, the key proteins in nucleosome and chromatin structure. HDAC inhibitors may act through the transcriptional reactivation of dormant tumor-suppressor genes. However, their pleiotropic nature leaves open the possibility that their well-known differentiation, cell-cycle arrest, and apoptotic properties are also involved in other functions associated with HDAC inhibition. Many phase I clinical trials indicate that HDAC inhibitors appear to be well-tolerated drugs. Thus, the field is ready for rigorous biologic and clinical scrutiny to validate the therapeutic potential of these drugs. HDAC inhibitors, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising drugs for cancer patients.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Archer SY, Meng S, Shei A, Hodin RA (1998) p21WAF1 is required for butyratemediated growth inhibition of human colon cancer cells. Proc Natl Acad Sci U S A 95:6791–6796
Ballestar E, Esteller M (2002) The impact of chromatin in human cancer: linking DNA methylation to gene silencing. Carcinogenesis 23:1103–1109
Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, Cigudosa JC, Huang TH, Esteller M (2003) Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. EMBO J 22:6335–6345
Blagosklonny MV, Robey R, Sackett DL, Du L, Traganos F, Darzynkiewicz Z, Fojo T, Bates SE (2002) Histone deacetylase inhibitors all induce p21 but differentially cause tubulin acetylation, mitotic arrest, and cytotoxicity. Mol Cancer Ther 1:937–941
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB (1999) Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet 21:103–107
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5740
Esteller M, Cordon-Cardo C, Corn PG, Meltzer SJ, Pohar KS, Watkins DN, Capella G, Peinado MA, Matias-Guiu X, Prat J, Baylin SB, Herman JG (2001) p14ARF silencing by promoter hypermethylation mediates abnormal intracellular localization of MDM2. Cancer Res 61:2816–221
Feinberg AP, Tycko B (2004) The history of cancer epigenetics. Nat Rev Cancer 4:143–153
Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, Iyer NG, Perez-Rosado A, Calvo E, Lopez JA, Cano A, Calasanz MJ, Colomer D, Piris MA, Ahn N, Imhof A, Caldas C, Jenuwein T, Esteller M (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37:391–400
Gui CY, Ngo L, Xu WS, Richon VM, Marks PA (2004) Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoterassociated proteins, including HDAC1. Proc Natl Acad Sci U S A 101:1241–1246
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD et al. (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci U S A 95:6870–6875
Iizuka M, Smith MM (2003) Functional consequences of histone modifications. Curr Opin Genet Dev 13:154–160
Jenuwein T, Allis CD (2001) Translating the histone code. Science 293:1074–1080
Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299
Jones PA, Baylin SB (2002) The fundamental role of epigenetic events in cancer. Nat Rev Genet 3:415–428
Martens JH, O’Sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005) The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J 24:800–812
Martin-Caballero J, Flores JM, Garcia-Palencia P, Serrano M (2001) Tumor susceptibility of p21Waf1/Cip1-deficient mice. Cancer Res 61:6234–6238
Pellikainen MJ, Pekola TT, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM (2003) p21WAF1 expression in invasive breast cancer and its association with p53, AP-2, cell proliferation, and prognosis. J Clin Pathol 56:214–220
Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14:R546–R551
Shoji T, Tanaka F, Takata T, Yanagihara K, Otake Y, Hanaoka N, Miyahara R, Nakagawa T, Kawano Y, Ishikawa S, Katakura H, Wada H (2002) Clinical significance of p21 expression in non-small-cell lung cancer. J Clin Oncol 20:3865–3871
Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45
Turner BM (2000) Histone acetylation and an epigenetic code. Bioessays 22:836–845
Turner BM (2005) Reading signals on the nucleosome with a new nomenclature for modified histones. Nat Struct Mol Biol 12:110–112
Villar-Garea A, Esteller M (2003) DNA demethylating agents and chromatinremodelling drugs: which, how and why? Curr Drug Metab 4:11–31
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2006 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Esteller, M. (2006). CpG Island Methylation and Histone Modifications: Biology and Clinical Significance. In: Berger, S.L., Nakanishi, O., Haendler, B. (eds) The Histone Code and Beyond. Ernst Schering Research Foundation Workshop, vol 57. Springer, Berlin, Heidelberg . https://doi.org/10.1007/3-540-37633-X_7
Download citation
DOI: https://doi.org/10.1007/3-540-37633-X_7
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-27857-3
Online ISBN: 978-3-540-37633-0
eBook Packages: MedicineMedicine (R0)