Targets of epigenetic therapy.

Chromatin is composed of both the double DNA strand and a scaffold of proteins, mainly formed by histone proteins. The basic structure of chromatin is the nucleosome that is composed of the core histones (histone H3 and histone H4) and 146 base pairs of DNA wrapped around them. Epigenetic regulation of gene promoter regions is crucial for gene expression control. In a chromatin-permissive state, most promoters that contain a CpG island are not methylated (M), and the lysine residues in histone tails are acetylated (AC). In this condition most genes can be expressed. In contrast, in its repressive state, which is associated with gene silencing, both methylation (M) of cytosine residues and deacetylation of histone tails can occur. In principle these two processes are enzymatically independent but can be functionally linked. DNA methylation is mediated by enzymes with DNA methyltransferase (DNMT) activity. No opposing activity to DNMT is currently known. Therefore, when DNA methylation is established, a phenomenon dependent on DNA replication, it is perpetuated in secondary cell divisions. DNMTs are inhibited by drugs such as 5-azacitidine and 5-aza-2′-deoxycitidine. The use of these drugs results, both in vivo and in vitro, in DNA hypomethylation and gene re-expression. In contrast, histone acetylation is a more dynamic process controlled by two opposing enzymatic activities: histone acetyltransferases (HAT) that introduce acetylation and histone deacetylases (HDAC) that induce deacetylation. HDAC inhibitors inhibit HDAC, thus rendering HAT unopposed, resulting in histone acetylation. Therefore the use of DNMT and HDAC inhibitors allows the conversion of a repressive chromatin state into a permissive one. How this results in clinical responses is unknown at the present time.