Rationale: Histone deacetylases (HDACs) are closely involved in cardiac reprogramming. Although the functional roles of the 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 alternate posttranslational activation mechanism of HDAC2 that involves acetylation of HDAC2 mediated by p300/CBP-associated factor (pCAF)/HDAC5.
Methods and Results: Hdac2 was acetylated in response to hypertrophic stresses in both cardiomyocytes and a mouse model. The 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. pCAF bound to Hdac2 and induced acetylation. The HDAC2 K75 residue was responsible for hypertrophic stress-induced acetylation. The acetylationresistant 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 anti-hypertrophic 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 pCAF and HDAC5 in the development of cardiac hypertrophy.