Small Molecule Inhibitors of Histone Deacetylases and Acetyltransferases as Potential Therapeutics in Oncology

Abstract Uncontrolled cell proliferation and resistance to apoptosis in cancer are, among others, regulated by posttranslational modifications of histone proteins. The most investigated type of histone modification is lysine acetylation. Histone acetyltransferases (HATs), acetylate histone lysine residues, and histone deacetylases (HDACs) remove acetyl residues from lysines, thereby influencing gene expression. Whereas HAT inhibitors are relatively undeveloped, four HDAC inhibitors (HDACi) reached the clinic for treatment of hematological cancers. HDACi induce apoptosis via inhibition of histone deacetylation and concomitant transcription of aberrantly silenced genes. Nevertheless, other mechanisms have also been described. Intriguingly, HDACs also target nonhistone proteins such as the nuclear factor κB (NF-κB) pathway, which is an important regulator of gene transcription for which a role in cancer has been implicated. Despite the studies that shed more light on the role of HDAC isoenzymes in the NF-κB pathway the challenge remains to develop isoenzyme-selective HDACi to target this pathway.