title: Casein kinase-2α1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart.
abstract: BACKGROUND
  Cardiac hypertrophy is characterized by transcriptional reprogramming of fetal gene expression, and histone deacetylases (HDACs) are tightly linked to the regulation of those genes. We previously demonstrated that activation of HDAC2, 1 of the class I HDACs, mediates hypertrophy. Here, we show that casein kinase-2α1 (CK2α1)-dependent phosphorylation of HDAC2 S394 is required for the development of cardiac hypertrophy.
  
  
  RESULTS
  Hypertrophic stimuli phosphorylated HDAC2 S394, which was necessary for its enzymatic activation, and therefore the development of hypertrophic phenotypes in rat neonatal cardiomyocytes or in isoproterenol-administered mice hearts. Transgenic mice overexpressing HDAC2 wild type exhibited cardiac hypertrophy, whereas those expressing phosphorylation-resistant HDAC2 S394A did not. Compared with that in age-matched normal human hearts, phosphorylation of HDAC2 S394 was dramatically increased in patients with hypertrophic cardiomyopathy. Hypertrophy-induced phosphorylation of HDAC2 S394 and its enzymatic activity were completely blocked either by CK2 blockers or by CK2α1 short interfering RNA. Hypertrophic stimuli led CK2α1 to be activated, and its chemical inhibitors blocked hypertrophy in both phenylephrine-treated cardiomyocytes and isoproterenol-administered mice. CK2α1-transgenic mice developed hypertrophy, which was attenuated by administration of trichostatin A, an HDAC inhibitor. Overexpression of CK2α1 caused hypertrophy in cardiomyocytes, whereas chemical inhibitors of both CK2 and HDAC as well as HDAC2 S394A blunted it. Hypertrophy in CK2α1-transgenic mice was exaggerated by crossing these mice with wild-type-HDAC2-overexpressing mice. By contrast, however, it was blocked when CK2α1-transgenic mice were crossed with HDAC2 S394A-transgenic mice.
  
  
  CONCLUSIONS
  We have demonstrated a novel mechanism in the development of cardiac hypertrophy by which CK2 activates HDAC2 via phosphorylating HDAC2 S394.
authors.affiliation: Medical Research Center for Gene Regulation, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju, South Korea.
authors.forename: Gwang Hyeon
authors.initials: GH
authors.lastname: Eom
authors.forename: Young Kuk
authors.initials: YK
authors.lastname: Cho
authors.forename: Jeong-Hyeon
authors.initials: JH
authors.lastname: Ko
authors.forename: Sera
authors.initials: S
authors.lastname: Shin
authors.forename: Nakwon
authors.initials: N
authors.lastname: Choe
authors.forename: Yoojung
authors.initials: Y
authors.lastname: Kim
authors.forename: Hosouk
authors.initials: H
authors.lastname: Joung
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.forename: Kwang-Il
authors.initials: KI
authors.lastname: Nam
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kee
authors.forename: Hyun
authors.initials: H
authors.lastname: Kook
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002312:Cardiomyopathy, Hypertrophic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics; D006352:Heart Ventricles / Q000201:enzymology* / Q000473:pathology; D056464:Histone Deacetylase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism*
chemical_list: D012694:Serine; D047390:Casein Kinase II; C533423:HDAC2 protein, human; D056464:Histone Deacetylase 2; D000409:Alanine