Targeting DNA methylation in cancer.
Cancer growth and metastasis require the coordinate change in gene expression of different sets of genes. While genetic alterations can account for some of these changes, many of the changes in gene expression observed in cancer are caused by epigenetic modifications. The epigenome consists of the chromatin and its modifications, the "histone code" as well as the pattern of distribution of covalent modifications of cytosines residing in the dinucleotide sequence CG by methylation. The normal pattern of distribution of DNA methylation is altered in cancer. A number of genes are regionally hypermethylated but many parts of the genome are hypomethylated. Hypermethylation of tumor suppressor genes is involved in silencing of strategic genes. DNA hypermethylation has received much attention and a number of clinical trials are underway with different inhibitors of DNA methylating enzymes. It is now becoming clear however that hypomethylation also plays a role in cancer by activating genes required for invasion and metastasis. The potential therapeutic implications of targeting DNA methylation in cancer are discussed.
Szyf
Moshe
M
Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Osler Promenade, Montreal PQ H3G 1Y6 Canada. moshe.szyf@mcgill.ca
D000107:Acetylation; D000818:Animals; D002843:Chromatin / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004032:Diet; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D015254:DNA Modification Methylases