Targeting cancers and metabolic disorders: The prospects of combining HDAC8 inhibitor and activator

Histone deacetylase-8 (HDAC8) is a unique member of class I Zn2+-dependent metalloenzyme of the classical histone deacetylases owing to its highly structural and kinetic characterization. Of interest, the diminution in the expression level of HDAC8 and or the impaired activity of the enzyme has been correlated with various pathophysiological events, such as neuroblastoma cancer, chronic obstructive pulmonary disease (COPD), Cornelia de Lange syndrome (CdLs) and other metabolic dysfunction. Notwithstanding, HDAC8 has been considered a high priority drug target, and because of the therapeutic benefits associated with HDAC8 inhibitors, the majority of the current research is geared toward searching for inhibitors of this enzyme. In addition, the potential for treating metabolic and age-related diseases by activation is gradually gaining attention. However, currently only a few researchers have reported on the biochemical significance of activators of HDAC8 and the information gathered further indicates that the combination of both activators and inhibitors could be a promising therapeutic strategy toward dissecting the role of HDAC8 in associated diseases. Therefore, the primary aim of this review is to elaborate on the prospects of combining HDAC8 activators and inhibitors for disease treatments due to HDAC8 diminution or impaired activity.