Targeting DNA methylation for epigenetic therapy - PubMed (original) (raw)

Review

Targeting DNA methylation for epigenetic therapy

Xiaojing Yang et al. Trends Pharmacol Sci. 2010 Nov.

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.

Copyright © 2010 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Figures

Figure 1

Figure 1. Epigenetic Regulation in Normal and Cancer Cells

Shown are schematic promoters. Arrows represent transcription start site (TSS); filled circles represent methylated CpG dinucleotide and empty circles represent unmethylated CpG dinucleotide. In normal cells (a), genes such as MLH1, CDKN2A are generally unmethylated and packaged with active modified histone proteins (e.g. H3K4me3) as well as histone variants (e.g. H2A.Z). These epigenetic modifications constitute an “open” chromatin structure which, with nucleosome depleted region (NDR), favoring transcription. In other genomic regions, such as in the repetitive elements, the CpG sites are methylated and thereby maintain a closed chromatin structure. In cancer cells (b), epigenetic modifications are disrupted. Besides cancer specific hypomethylation (e.g. in repetitive sequence), there are two interrelated epigenetic mechanisms to repress gene expression. Some genes (e.g.FBXO32) could be recognized by polycomb proteins, such as EZH2, which catalyses H3K27 methylation, and are consequently repressed. By contrast, CpG sites within gene promoters could undergo _de nov_o methylation by DNMT3A/B, which are compartmentalized to these regions to complete the methylation process. The methylated CpG sites attract methyl-binding proteins such as MBD, which is coupled with HDAC proteins to remove histone acetylation as well as histone methyltransferase to methylate H3K9. Associated with all repressive factors shown, nucleosomes cover the promoter region, generating a tightly closed chromatin status to shut down gene expression.

Figure 2

Figure 2. Chemical Structure of DNMT inhibitors

A. nucleoside analogues B. non-nucleoside analogues.

Figure 2

Figure 2. Chemical Structure of DNMT inhibitors

A. nucleoside analogues B. non-nucleoside analogues.

Figure 3

Figure 3. Metabolism pathway and action mechanism of 5-Azanucleosides

A. Human Concentrated Nucleoside Transporters 1 (hCNT1) facilitates the entry of 5-Aza-CR and 5-Aza-CdR into cells where they are phosphorylated by uridine-cytidine kinase and deoxycytidine kinase respectively. 5-Aza-CMP and 5-Aza-dCMP are subsequently phosphorylated into their active triphosphate forms. 5 Aza-dCR can be incorporated solely into DNA, whereas 5-Aza-CR can be incorporated into RNA as well as DNA following the reduction of its 5-Aza-CDP form to the 5-Aza-dCDP form. Incorporation of 5-Azanucleosides into DNA induces hypomethylation of the daughter DNA strands whereas incorporation of 5-Aza-CR into RNA disrupts crucial cellular process such as protein translation and causes ribosomal disassembly. 5-Azanucleosides, however, are also very unstable and can be deaminated to inactive uridine. B. Schematic working model of 5-Azanucleosides. During DNA replication, 5-Azanucleosides are incorporated into DNA and trap DNMTs, which are subsequently targeted for proteosomal degradation. DNA containing azanucleosides are hemimethylated after the first round of DNA replication and become fully demethylated after several rounds of replication. Using hypomethylation agents, the silenced epigenetic modifications could be switched to an active status (eg.H3K4me3 and AcH3)

Similar articles

Cited by

References

    1. Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–692. - PMC - PubMed
    1. Lister R, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009;462:315–322. - PMC - PubMed
    1. Suzuki MM, Bird A. DNA methylation landscapes: provocative insights from epigenomics. Nat Rev Genet. 2008;9:465–476. - PubMed
    1. Takai D, Jones PA. Comprehensive analysis of CpG islands in human chromosomes 21 and 22. Proc Natl Acad Sci U S A. 2002;99:3740–3745. - PMC - PubMed
    1. Wang Y, Leung FC. An evaluation of new criteria for CpG islands in the human genome as gene markers. Bioinformatics. 2004;20:1170–1177. - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources