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Given the skyrocketing costs to develop new drugs, repositioning of approved drugs, such as histone deacetylase (HDAC) inhibitors, may be a promising strategy to develop novel therapies. However, a gap exists in the understanding and advancement of these agents to meaningful translation for which new indications may emerge. To address this, we performed systems-level analyses of 33 independent HDAC inhibitor microarray studies. Based on network analysis, we identified enrichment for pathways implicated in metabolic syndrome and diabetes (insulin receptor signaling, lipid metabolism, immunity and trafficking). Integration with ENCODE ChIP-seq datasets identified suppression of EP300 target genes implicated in diabetes. Experimental validation indicates reversal of diabetes-associated EP300 target genes in primary vascular endothelial cells derived from a diabetic individual following inhibition of HDACs (by SAHA), EP300, or EP300 knockdown. Our computational systems biology approach provides an adaptable framework for the prediction of novel therapeutics for existing disease.

Histone deacetylase inhibitors are emerging as a new class of cancer chemotherapeutics and already are being heralded as the first anti-cancer drugs targeting the epigenome. Through histone hyperacetylation-mediated changes in chromatin conformation and gene expression, histone deacetylase inhibitors induce differentiation, cell cycle arrest, apoptosis, growth inhibition and cell death, which are more pronounced in transformed cell-lines than in normal cells. Additional anti-cancer effects of HDAC inhibitors include inhibition of migration, invasion and angiogenesis in vivo. Indeed, clinical anti-cancer activity has been observed using HDAC inhibitors as single agents or in combination with conventional chemotherapeutics, in phase I and II trials. Furthermore, numerous preclinical studies are suggesting a potential clinical role for HDAC inhibitors in radiotherapy either as radiation sensitizers or protectors. In this article the molecular basis for the clinical potential of HDAC inhibitors, either as stand alone cancer therapeutics or in combination with other chemotherapy agents or ionizing radiation will be overviewed.