Targeting DNA methylation in cancer.
There is overwhelming evidence that DNA methylation patterns are altered in cancer. Methylation of CG-rich islands in regulatory regions of genes marks them for transcriptional silencing. Multiple genes, which confer selective advantage upon cancer cells such as tumor suppressors, adhesion molecules, inhibitors of angiogenesis and repair enzymes are silenced. In parallel, tumor cell genomes are globally less methylated than their normal counterparts. In contrast to regional hypermethylation, this loss of methylation in cancer cells occurs in sparsely distributed CG sequences. We now understand that DNA methylation machineries might include a number of DNA methyltransferases, proteins that direct DNA methyltransferases to specific promoters, chromatin modifying enzymes as well as demethylases. There is also data to suggest that pharmacological down regulation of some members of the DNA methylation machinery could inhibit cancer in vitro, in vivo and in clinical trials. Understanding which functions of DNA methylation machinery are critical for cancer is essential for the design of inhibitors of the DNA methylation machinery as anticancer agents. This review discusses the possible role of DNA methyltranferases and demethylases in tumorigenesis and the possible pharmacological and therapeutic implications of the DNA methylation machinery.
Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal, Que, Canada H3G 1Y6. mszyf@pharma.mcgill.ca
Moshe
M
Szyf
D000818:Animals; D019175:DNA Methylation; D020868:Gene Silencing; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*