title: Regulation of acetylation of histone deacetylase 2 by p300/CBP-associated factor/histone deacetylase 5 in the development of cardiac hypertrophy.
abstract: BACKGROUND
  Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of class I and class IIa HDACs are well established, the significance of interclass crosstalk in the development of cardiac hypertrophy remains unclear.
  
  
  OBJECTIVE
  Recently, we suggested that casein kinase 2α1-dependent phosphorylation of HDAC2 leads to enzymatic activation, which in turn induces cardiac hypertrophy. Here we report an alternative post-translational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor/HDAC5.
  
  
  RESULTS
  Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. Acetylation was reduced by a histone acetyltransferase inhibitor but was increased by a nonspecific HDAC inhibitor. The enzymatic activity of Hdac2 was positively correlated with its acetylation status. p300/CBP-associated factor bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress-induced acetylation. The acetylation-resistant Hdac2 K75R showed a significant decrease in phosphorylation on S394, which led to the loss of intrinsic activity. Hdac5, one of class IIa HDACs, directly deacetylated Hdac2. Acetylation of Hdac2 was increased in Hdac5-null mice. When an acetylation-mimicking mutant of Hdac2 was infected into cardiomyocytes, the antihypertrophic effect of either nuclear tethering of Hdac5 with leptomycin B or Hdac5 overexpression was reduced.
  
  
  CONCLUSIONS
  Taken together, our results suggest a novel mechanism by which the balance of HDAC2 acetylation is regulated by p300/CBP-associated factor and HDAC5 in the development of cardiac hypertrophy.
authors: From the Department of Pharmacology (G.H.E., J.-K.K., H.K.) and Medical Research Center for Gene Regulation (G.H.E., Y.S.N., N.C., H.-K.M., H.K.), Chonnam National University Medical School, Gwangju, Republic of Korea; Global Research Laboratory and College of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea (J.G.O., W.J.P.); Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea (E.-K.Y., I.-K.L.); Division of Clinical Pharmacology, Chonnam National University Hospital, Gwangju, Republic of Korea (G.K., J.-K.K.); Department of Nuclear Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea (V.H.N., J.-J.M.); and Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX (R.B.-D., E.N.O.).
authors: Gwang Hyeon
authors: GH
authors: Eom
authors: Yoon Seok
authors: YS
authors: Nam
authors: Jae Gyun
authors: JG
authors: Oh
authors: Nakwon
authors: N
authors: Choe
authors: Hyun-Ki
authors: HK
authors: Min
authors: Eun-Kyung
authors: EK
authors: Yoo
authors: Gaeun
authors: G
authors: Kang
authors: Vu Hong
authors: VH
authors: Nguyen
authors: Jung-Joon
authors: JJ
authors: Min
authors: Jong-Keun
authors: JK
authors: Kim
authors: In-Kyu
authors: IK
authors: Lee
authors: Rhonda
authors: R
authors: Bassel-Duby
authors: Eric N
authors: EN
authors: Olson
authors: Woo Jin
authors: WJ
authors: Park
authors: Hyun
authors: H
authors: Kook
mesh_terms: D000107:Acetylation; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
keywords: acetylation; cardiomyopathy, hypertrophic; histone deacetylase 2; histone deacetylase 5, mouse; p300-CBP–associated factor; protein processing, post-translational