Epigenetic therapy of cancer

Together with genetic alterations, aberrant epigenetic regulation of gene expression also plays a major role in the development of many diseases, including cancer. Overall, when compared to normal cells, the genome of malignant cells is characterized by global DNA hypomethylation and histone hypoacetylation. Considering the significance of DNA methylation and histone acetylation in the initiation and progression of human cancer, epigenetic modifications are identified as novel therapeutic targets. In contrast to genetic alterations, epigenetic changes in cancer are potentially reversible. This fact resulted in the development of pharmacologic inhibitors of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs). These compounds can reverse epigenetic silencing of tumor suppressor genes by inducing the demethylation of DNA and histone acetylation, resulting in reactivation of these genes in tumor cells and restoration of crucial cellular pathways. However, it is still unclear whether the majority of HDAC inhibitors' effects are the result of alterations of histone acetylation patterns or changes in growth regulatory pathways deregulated by the increased acetylation of non-histone proteins. Although DNMT and HDAC inhibitors can be active as monotherapy, it is widely accepted that the most effective clinical application of epigenetic modulators may be in combination with other agents. Much remains to be elucidated about the epigenome, regarding its role and its dysregulation in cancer, and therefore future research is needed to provide sufficient information for optimization of epigenetic therapy in clinical practice.