Posttranslational modifications of class I histone deacetylases in muscular diseases
  • Hyun Kook
  • SLS Colloquia / 2017.09.21(Thu), 04:00pm / Room N104, Bldg110

Department of Pharmacology, National Research Laboratory for Heart and Muscle Diseases, Chonnam National University Medical School, Gwangju 501-746, Korea


Histone deacetylases (HDAC) are one group of the important epigenetic regulators in homeostasis and in pathophysiology. It removes acetyl moiety from histones to repress the transcription by tightening the nucleosome. Their deacetylase activities are finely regulated by their posttranslational modifications (PTMs). At least 18 different HDACs are discovered in mammals and divided into 4 classes based on their structures. Four HDACs of HDAC1/2/3/8 belong to class I HDACs. For last decade, my laboratory has worked on the roles of class I HDACs: 1) HDAC2 and its PTM in the development of cardiac hypertrophy/heart failure, 2) HDAC1 polyubiquitination in vascular calcification, 3) HDAC1 sumoylation and its regulation of skeletal muscle specific transcription factors. In this session, I will briefly review our recent advances in the PTM of class I HDAC in those muscular diseases.


Diverse stresses lead the heart to a remodeling process characterized by myocyte hypertrophy, death, and fibrosis, which often results in heart failure. Our research group observed that HDAC inhibitors prevent cardiac hypertrophy (J Clin Invest 2003; Circulation 2006; Circ J 2010). We also showed that activation of HDAC2, one of class I HDACs, is indispensable for cardiac hypertrophy (Circ Res 2008) and that casein kinase 2-induced phosphorylation of HDAC2 S394 residue is required (Circulation 2011) and that Kruppel-like factor 4 works as downstream of HDAC2 (J Mol Cell Cardiol 2009). We observed that the acetylation of HDAC2 K75 is an important signal to relay the cardiac hypertrophy and that HDAC2 K75 acetylation precedes HDAC2 S394 phosphorylation, which is balanced by pCAF and HDAC5 (Circ Res 2014). As a novel phosphorylation regulation mechanism, we propose that protein phosphatase 2A (PP2A) removes phosphate from HDAC2, which was prevented by phosphor-HDAC2-specific binding of heat shock protein 70.


Vascular calcification (VC) often associates with many cardiovascular and metabolic diseases. Recently we observed that MDM2-induced ubiquitination of HDAC1 mediates VC. Loss of HDAC1 activity enhanced VC in vivo and in vitro. Calcification stresses induced MDM2 E3 ligase, which resulted in HDAC1 K74 ubiquitination. MDM2 enhanced VC, whereas loss of MDM2 blunted it. These results demonstrate a previously unknown ubiquitination pathway as well as the involvement of HDAC1 in VC (Nat Comm 2016). Sumoylation, acetylation, and microRNA, an alternative epigenetic regulators, are actively involved in vascular diseases (Atherosclerosis 2013; Cell Signal 2015; FEBS Lett 2017).


Together with HDAC1, Ret finger protein (RFP) induces transcriptional repression (Cell Death Dis 2012) and polyubiquitination of MyoD (Cell Signal 2014) to prevent skeletal muscle differentiation. We further observed that sumoylation of HDAC1 is enhanced in the differentiation. This sumoylation induces dissociation of HDAC1 from MyoD, which further enhance the skeletal muscle differentiation (Exp Mol Med 2017).


Taken together, PTMs of class I HDACs are critical in the normal physiology and the development of diverse diseases in the sarcomeric and smooth muscles.