DNA methylation and cancer therapy.
Vertebrate DNA is modified by methyl moieties at the 5'-position of cytosine rings residing in the di-nucleotide sequence CpG. Approximately 80% of CpG dinucleotide sequences are methylated. The pattern of distribution of methylated CGs is cell-type specific and correlates with gene expression programming and chromatin structure. Three kinds of seemingly contradictory aberrations in DNA methylation are observed in cancer, global hypomethylation, and regional hypermethylation and deregulated level of expression of DNA methyltransferases. It was previously proposed that the DNA methylation machinery is a candidate target for anticancer therapy. Inhibition of hypermethylation was the first therapeutic target. However, recent data suggests that inhibition of DNA methylation might have untoward effects such as induction of genes involved in metastasis. This review discusses the relative role of the three levels of alteration in the DNA methylation in cancer, proposes a unified hypothesis on the relative roles of increased DNA methyltransferase as well as the coexistence of hypo -and hyper- methylation in cancer and its possible implications on anticancer therapy.
Szyf
Moshe
M
Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Promenade, Quebec H3G 1Y6, Montreal, Canada. mszyf@pharma.mcgill.ca
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D002843:Chromatin; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases