Targeting epigenetic networks with polypharmacology: a new avenue to tackle cancer

Abstract

The term ‘epigenetic’ fuses old and new concepts that refer to the modulation of gene expression in cellular heritability, fate, development and programming–reprogramming other than the DNA sequence itself. Epigenetic control of transcription is regulated by enzymes that mediate covalent modifications at gene-regulatory regions and histone proteins around which chromosomal DNA is wound. Many of the enzymes that mediate chromatin epigenetic reactions are deregulated in diseases such as cancer. Thus, small-molecule inhibitors that target chromatin-modifying enzymes represent a novel option for treatment, and DNA methyltransferase and histone deacetylase inhibitors have been approved for cancer treatment. Moreover, other classes of epi-enzymes (MS-275, SAHA) have been demonstrated to have strong disease association, and are currently being targeted for modulation. An epigenetic poly-pharmacological approach targeting multiple chromatin-modifying enzymes may represent a ‘smart’ option to treat cancer versus the current view on the selective and single pharmacological targeting of epigenetic enzymes.