Epigenetic regulation of gene expression as an anticancer drug target

Epigenetic processes play a key regulatory role in cancer. Hypermethylation in the CpG islands of the promoter regions of many tumour suppressor genes leads to the recruitment of co-repressors, altered chromatin structure, and ultimately transcriptional silencing. Key components in the regulation of DNA methylation are DNA methyltransferases (DNMT1, 2, 3A and 3B) and methyl CpG-binding proteins, which recognize methyl cytosine residues and recruit transcriptional repressor complexes, including histone deacetylases (HDAC). DNMT1 is responsible for the maintenance of DNA methylation patterns during replication. Inhibitors of this enzyme may potentially lead to DNA hypomethylation, and re-expression of tumour suppressor genes. Several DNMT inhibitors are currently being evaluated in preclinical and clinical studies, include various analogues of adenosine, cytidine or deoxycytidine. However, such drugs have had limited clinical success, perhaps because of cytotoxicity associated with their incorporation into DNA. Non-nucleoside small molecule inhibitors of DNMTs can directly block DNMT activity, and may be able to circumvent this cytotoxicity. Post-translational modifications of histones play a key role, not only in regulating chromatin structure and gene expression, but also in genomic stability. Histone acetylation (HAT) and histone deacetylation (HDAC) affect chromatin condensation, with concomitant effects on gene transcription. A further range of compounds is being evaluated for clinical use as HDAC inhibitors, including hydroxamic acids such as Trichostatin A (TSA) and Suberoyl anilide bishydroxamide (SAHA). MicroRNAs are also found to play a key role in cancer development, and novel approaches to their regulation may provide a susceptible anticancer drug target. Because of the interdependence of epigenetic processes, combinations of these approaches may have maximum clinical efficacy.