J.P. Issa

Neoplastic cells have numerous clonal changes in gene expression when compared to normal cells. Some of these differences in gene expression are permanent, unrelated to structural alterations in DNA, and have been referred to as epigenetic changes. One of the common mediators of epigenetic changes in human cells is a biochemical process termed DNA methylation that adds a methyl group to the cytosine base. DNA methylation of gene regulatory areas can result in permanent loss of gene expression and can be found on the inactive X-chromosome in normal female cells, and on several genes (including tumor-suppressor genes) in malignant cells. DNA methylation is functionally linked to histone modifications, another major molecular mechanism of epigenetic information.

Epigenetic changes in neoplastic epithelial cells can often be observed, to a smaller degree, in aging normal-appearing epithelium as well. This has led to the hypothesis that epigenetic changes accompany or result from DNA aging in some cells, and that age-related epigenetic changes predispose to proliferative or degenerative diseases associated with the aging process in humans.

Inhibition of DNA methylation and/or histone modifications can reverse epigenetic silencing, leading to restoration of gene expression and a potential therapeutic effect in cancer cells. 5-aza-2’-deoxycytidine (DAC, Decitabine) is a cytosine analogue that incorporates into DNA, traps and depletes all known DNA methyltransferase enzymes, resulting in loss of DNA methylation and gene reactivation. Treatment of cancer cells with DAC also leads to rapid changes in histone modifications (methylation, acetylation) that contribute to restoration of gene expression. DAC has experienced a clinical resurgence over the past few years, and early clinical trials suggest promising anti-cancer activity, mediated in part by demethylation rather than cytotoxicity. Histone deacetylase inhibitors such as Depsipeptide and SAHA are also currently in clinical trials as anti-neoplastic agents, and early reports also suggest efficacy in selected cases. DAC, Depsipeptide and SAHA are prototypes of a class of epigenetic-acting agents that promise to introduce epigenetic therapy into the management of cancer and, possibly, other age-related diseases as well.

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