DNMT cooperativity--the developing links between methylation, chromatin structure and cancer.
Controversy has reigned for some time over the biological connection between DNA methylation and cancer. For this reason, the methylation mechanism responsible for increased cancer risk has received greater attention in recent years. Tumor suppressor genes are often hypermethylated resulting in gene silencing. Although some have questioned this interpretation of the link between methylation and cancer, it appears that both hypermethylation and hypomethylation events can create epigenetic changes that can contribute to cancer development. Recent studies have shown that the methyltransferases DNMT1 and DNMT3b cooperatively maintain DNA methylation and gene silencing in human cancer cells. Disruption of the human DNMT3b only slightly reduces the overall global DNA methylation; however, demethylation was markedly potentiated when both DNMT1 and DNMT3b were simultaneously deleted. The results to these experiments provide compelling evidence towards a role for DNA methylation in cancer. This review discusses the current understanding of cancer-epigenetic information and highlights recent studies that connect the methylation machinery and chromatin remodelling with cancer susceptibility.
The Alfred Medical Research and Education Precinct (AMREP), Baker Medical Research Institute, Epigenetics in Human Health and Disease Laboratory, Second Floor, Commercial Road, Prahran, Victoria 3181, Australia. assam.el-osta@baker.edu.au
Assam
A
El-Osta
D000818:Animals; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
D002843:Chromatin; D004247:DNA; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006657:Histones; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human