Epigenetic therapy of cancer: past, present and future

Abstract

The past decade has seen a rapid emergence of epigenetics as a major contributor to carcinogenesis. Aberrations in the normal DNA methylation patterns and histone modifications have been recognized as targets for therapy which, unlike conventional chemotherapy, aim to revert the abnormal state of malignant cells to a more normal condition. Demethylating agents that belong to a group of nucleoside analogues all have cytosine-ring modifications that allow each compound to form a covalent complex with a DNA methyltransferase, thereby inhibiting further methylation. Other DNA-methylation inhibitors belong to a group of non-nucleoside analogues whose mechanism of inhibition is not well known. DNA methylation inhibitors have the disadvantages of lacking specificity and causing genome-wide hypomethylation which might activate appropriately silent genes and/or initiate genome instability, leading to undesirable consequences. These problems will be circumvented with more specific drugs directed to specific regions of the genome. It is anticipated that these drugs would be available in the form of chemically synthesized small molecules, which are more effective than cytidine analogues because they do not require incorporation into DNA and bind directly to the catalytic site of the DNA methyl transferases. Histone deacetylase (HDAC) inhibitors are divided into four groups but hybrid molecules combining functional groups with superior inhibitory effects have already been synthesized. Compounds that inhibit individual members of all HDAC classes will be synthesized in the future. Lysine methylation is another histone modification which could be essential in regulating gene expression but its use as a target for epigenetic therapy might not come to fruition until more complete classification of this type of epigenetic regulation is possible.