Targeting DNA Methylation for Epigenetic Therapy

Overview

Journal Trends Pharmacol Sci

Specialty Pharmacology

Date 2010 Sep 18

PMID 20846732

Citations 130

Authors

Xiaojing Yang

Fides Lay

Han Han

Peter A Jones

Affiliations

Soon will be listed here.

Abstract

Patterns of DNA methylation are established during embryonic development and faithfully copied through somatic cell divisions. Based on current understanding of DNA methylation and other interrelated epigenetic modifications, a comprehensive view of the 'epigenetic landscape' and cancer epigenome is evolving. The cancer methylome is highly disrupted, making DNA methylation an excellent target for anticancer therapies. During the last few decades, an increasing number of drugs targeting DNA methylation have been developed to increase efficacy and stability and to decrease toxicity. The earliest and the most successful epigenetic drug to date, 5-Azacytidine, is currently recommended as the first-line treatment of high-risk myelodysplastic syndromes (MDS). Encouraging results from clinical trials have prompted further efforts to elucidate epigenetic alterations in cancer, and to subsequently develop new epigenetic therapies. This review delineates the latest cancer epigenetic models, the recent discovery of hypomethylation agents as well as their application in the clinic.

Citing Articles

Epigenetic Modulation Directs Recovery Post LASIK and SMILE Surgery: An Experimental Study.

Shetty R, Khamar P, Kannan R, Thacker P, Kumar N, Ghosh A Life (Basel). 2025; 15(2).

PMID: 40003656 PMC: 11856829. DOI: 10.3390/life15020246.

Epigenetic marvels: exploring the landscape of colorectal cancer treatment through cutting-edge epigenetic-based drug strategies.

Tahghighi A, Seyedhashemi E, Mohammadi J, Moradi A, Esmaeili A, Pornour M Clin Epigenetics. 2025; 17(1):34.

PMID: 39987205 PMC: 11847397. DOI: 10.1186/s13148-025-01844-w.

Identification of SDG gene family members and exploration of flowering related genes in different cultivars of chrysanthemums and their wild ancestors.

Han T, Khan M, Wang Y, Tan W, Li C, Ai P BMC Plant Biol. 2024; 24(1):813.

PMID: 39210253 PMC: 11360836. DOI: 10.1186/s12870-024-05465-y.

NEUROD1: transcriptional and epigenetic regulator of human and mouse neuronal and endocrine cell lineage programs.

Pavlinkova G, Smolik O Front Cell Dev Biol. 2024; 12:1435546.

PMID: 39105169 PMC: 11298428. DOI: 10.3389/fcell.2024.1435546.

The role of tumor-associated macrophages in tumor immune evasion.

Huang R, Kang T, Chen S J Cancer Res Clin Oncol. 2024; 150(5):238.

PMID: 38713256 PMC: 11076352. DOI: 10.1007/s00432-024-05777-4.

References

Chuang J, Warner S, Vollmer D, Vankayalapati H, Redkar S, Bearss D . S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010; 9(5):1443-50. PMC: 2868087. DOI: 10.1158/1535-7163.MCT-09-1048. View

Kouzarides T . Chromatin modifications and their function. Cell. 2007; 128(4):693-705. DOI: 10.1016/j.cell.2007.02.005. View

Rauch T, Zhong X, Wu X, Wang M, Kernstine K, Wang Z . High-resolution mapping of DNA hypermethylation and hypomethylation in lung cancer. Proc Natl Acad Sci U S A. 2007; 105(1):252-7. PMC: 2224196. DOI: 10.1073/pnas.0710735105. View

Billam M, Sobolewski M, Davidson N . Effects of a novel DNA methyltransferase inhibitor zebularine on human breast cancer cells. Breast Cancer Res Treat. 2009; 120(3):581-92. PMC: 3901992. DOI: 10.1007/s10549-009-0420-3. View

Velez-Garcia E, VOGLER W, Bartolucci A, ARKUN S . Twice weekly 5-azacytidine infusion in dissmeinated metastatic cancer: a phase II study. Cancer Treat Rep. 1977; 61(9):1675-7. View

Li B, Carey M, Workman J . The role of chromatin during transcription. Cell. 2007; 128(4):707-19. DOI: 10.1016/j.cell.2007.01.015. View

Fenaux P, Mufti G, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A . Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009; 10(3):223-32. PMC: 4086808. DOI: 10.1016/S1470-2045(09)70003-8. View

Silverman L, Demakos E, Peterson B, Kornblith A, Holland J, Odchimar-Reissig R . Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002; 20(10):2429-40. DOI: 10.1200/JCO.2002.04.117. View

Cedar H, Bergman Y . Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009; 10(5):295-304. DOI: 10.1038/nrg2540. View

10.

Lemaire M, Momparler L, Raynal N, Bernstein M, Momparler R . Inhibition of cytidine deaminase by zebularine enhances the antineoplastic action of 5-aza-2'-deoxycytidine. Cancer Chemother Pharmacol. 2008; 63(3):411-6. DOI: 10.1007/s00280-008-0750-6. View

11.

Oki Y, Kantarjian H, Gharibyan V, Jones D, OBrien S, Verstovsek S . Phase II study of low-dose decitabine in combination with imatinib mesylate in patients with accelerated or myeloid blastic phase of chronic myelogenous leukemia. Cancer. 2007; 109(5):899-906. DOI: 10.1002/cncr.22470. View

12.

Arita K, Ariyoshi M, Tochio H, Nakamura Y, Shirakawa M . Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature. 2008; 455(7214):818-21. DOI: 10.1038/nature07249. View

13.

Jones P, Liang G . Rethinking how DNA methylation patterns are maintained. Nat Rev Genet. 2009; 10(11):805-11. PMC: 2848124. DOI: 10.1038/nrg2651. View

14.

Flotho C, Claus R, Batz C, Schneider M, Sandrock I, Ihde S . The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009; 23(6):1019-28. DOI: 10.1038/leu.2008.397. View

15.

Yoo C, Chuang J, Byun H, Egger G, Yang A, Dubeau L . Long-term epigenetic therapy with oral zebularine has minimal side effects and prevents intestinal tumors in mice. Cancer Prev Res (Phila). 2009; 1(4):233-40. PMC: 6959547. DOI: 10.1158/1940-6207.CAPR-07-0008. View

16.

Yang A, Doshi K, Choi S, Mason J, Mannari R, Gharybian V . DNA methylation changes after 5-aza-2'-deoxycytidine therapy in patients with leukemia. Cancer Res. 2006; 66(10):5495-503. DOI: 10.1158/0008-5472.CAN-05-2385. View

17.

Wang Z, Zang C, Rosenfeld J, Schones D, Barski A, Cuddapah S . Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genet. 2008; 40(7):897-903. PMC: 2769248. DOI: 10.1038/ng.154. View

18.

Ordway J, Budiman M, Korshunova Y, Maloney R, Bedell J, Citek R . Identification of novel high-frequency DNA methylation changes in breast cancer. PLoS One. 2007; 2(12):e1314. PMC: 2117343. DOI: 10.1371/journal.pone.0001314. View

19.

Nan X, Ng H, Johnson C, Laherty C, Turner B, Eisenman R . Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature. 1998; 393(6683):386-9. DOI: 10.1038/30764. View

20.

Zlatanova J, Thakar A . H2A.Z: view from the top. Structure. 2008; 16(2):166-79. DOI: 10.1016/j.str.2007.12.008. View