Abstract
Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. Whilst it has been established that HDACs regulate many cellular processes, far less is known about the regulation of these enzymes themselves. Here, we show that HDAC8 is allosterically regulated by shifts in populations between exchanging states. An inactive state is identified, which is stabilised by a range of mutations and resembles a sparsely-populated state in equilibrium with active HDAC8. Computational models show that the inactive and active states differ by small changes in a regulatory region that extends up to 28 Å from the active site. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, thus suggesting a general mechanism. The presented results pave the way for the development of allosteric HDAC inhibitors and regulators to improve the therapy for several disease states.
Highlights
Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology
Tight-binding, substrate-competitive HDAC inhibitors were used to provide perturbations near the HDAC8 active site and concomitant changes observed in methyl-TROSY spectra report directly on how these perturbations propagated throughout the enzyme
Binding of suberoylanilide hydroxamic acid (SAHA) to HDAC8 resulted in small chemical shift changes in the methyl-TROSY NMR spectra, Fig. 1d and Supplementary Fig. 3
Summary
Histone deacetylases (HDACs) are key enzymes in epigenetics and important drug targets in cancer biology. The regulatory allosteric region identified here in HDAC8 corresponds to regions in other class I HDACs known to bind regulators, suggesting a general mechanism. 1234567890():,; Histone deacetylases (HDACs) have well−established roles in epigenetics and tumour biology, and new cellular roles of these enzymes are being revealed at a remarkable pace. This has led to proposals to target HDACs for the treatment of diseases ranging from cancers to neurodegenerative disorders[1,2,3,4,5]. Introducing local perturbations in the substrate-binding site by tight-binding inhibitors result in changes near the distal regulatory region whilst mutations introduced in the regulatory region lead to downregulation of HDAC8 activity. As the identified allosteric region coincides with regulatory interactions and regulatory post-translational modifications, these results represent a platform to rationalise how the activity of histone deacetylases can generally be modulated
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