Abstract 12882: P300/CBP-Associated-Factor Mediated Acetylation of Histone Deacetylase 2 K75 Induces Cardiac Hypertrophy
BACKGROUND: Cardiac hypertrophy is characterized by increase of individual cell size without cell division, which is an adaption to various hemodynamic or neurohormonal demands. Reactivation of fetal gene program is a notable phenotype. Histone deacetylases (HDACs) are tightly involved with the regulation of cardiac reprogramming. Recently, we elucidated that phosphorylation of HDAC2 S394 by casein kinase-2α1 leads enzymatic activation of HDAC2, which plays an important role in the development of cardiac hypertrophy. Here, we suggest another regulation mechanism, the p300/CBP-associated factor (pCAF)-mediated acetylation of Hdac2.
METHODS AND RESULTS: Acetylation of HDAC2 was increased in vitro (endothelin-administered rat neonatal cardiomyocytes) or in vivo (isoproterenol-treated mice hearts) model. Hdac2 acetylation was decreased by garcinol, a histone acetyl transferase (HATase) inhibitor, but increased by trichostatin A (TSA), a nonspecific histone deacetylase (HDAC) inhibitor. The HDAC2 acetylation status showed positive correlation with its enzymatic activity. Among the acetyl transferases tested, pCAF physically interacted with HDAC2 and acetylated HDAC2. Most of HDAC2 acetylation was abolished when the lysine 75 was substituted with arginine. HDAC2 K75R mutant showed decrease in intrinsic activity and pCAF-mediated increase in activity was not observed in the acetylation-resistant mutant. HDAC2 K75R mutant elicited decrease in phosphorylation of S394 and failed to induce hypertrophic phenotype. HDAC2 acetylation was not increased by apicidin, a specific Class I HDAC inhibitor, however it was increased by TSA, suggesting the involvement of class II HDAC in the acetylation of HDAC2 . Among the Class IIa HDACs tested, HDAC5 deacetylated HDAC2, which was completely reversed by both TSA and HDAC5 siRNA. Inhibition of HDAC5 subcellular shuttling by leptomycin B blocked both acetylation and subsequent phosphorylation of HDAC2.
CONCLUSIONS: Here we suggest a novel regulation mechanism of HDAC2 activity by modulating its acetylation status with pCAF and HDAC5 in the development of cardiac hypertrophy.
- © 2012 by American Heart Association, Inc.