Histone Deacetylase Inhibitors Modulating Non-epigenetic Players: The Novel Mechanism for Small Molecule Based Therapeutic Intervention

Abstract

Histone deacetylases (HDACs) play a crucial role in regulating the expression and activity of myriad of proteins involved in tumour onset and progression. HDAC activity results in a nonpermissive chromatin conformation by erasing acetyl moiety from histone substrates culminating in transcriptional repression of those genes having significant role in tumourigenesis. Apart from histones, HDACs deacetylate a variety of non-histone proteins including transcription factors involved in controlling cell growth, differentiation and apoptosis. Histone deacetylase inhibitors (HDACi) are small-molecules restraining HDACs and hence modulating their biological activity. Emerging evidences suggest that acetylation of non-histone proteins plays a critical role in various cellular processes including mRNA stability, protein localization and degradation. Abnormal turnover or expression of non-histone proteins like nuclear factor- kappaB (NF-κB), heat shock protein 90 (HSP90) and frataxin fuels various diseases including cancer. The present article explores the therapeutic role of HDACi with special emphasis on modulation of clinically relevant non-histone molecular targets. Extensive details regarding the non-histone proteins and their deregulation in disease states have also been provided. Moreover, the underlying molecular mechanism triggered by HDACi to overcome disease states by modulating the predefined targets has also been illuminated. The article strongly suggests the promising use of HDACi in therapeutic intervention against complications arising due to non-histone protein deregulation.

Keywords: Acetylation; HATs; HDACi; HDACs; deacetylation; histone proteins; non-histone proteins..