J Clin Invest. 2020 Jun 1;130(6):2811-2813. doi: 10.1172/JCI137074.
Class IIa histone deacetylases (HDACs) repress cardiomyocyte hypertrophy through association with the prohypertrophic transcription factor (TF) myocyte enhancer factor-2 (MEF2). The four class IIa HDACs - HDAC4, -5, -7, and -9 - are subject to signal-dependent phosphorylation by members of the Ca2+/calmodulin-dependent protein kinase (CaMK) group. In response to stress, HDAC4, HDAC5, and HDAC9 undergo phosphorylation-induced nuclear export in cardiomyocytes, freeing MEF2 to stimulate progrowth genes; it was generally assumed that HDAC7 is also antihypertrophic. However, in this issue of the JCI, Hsu and colleagues demonstrate that, in sharp contrast to the other class IIa HDACs, HDAC7 is constitutively localized to the cardiomyocyte cytoplasm, where it promotes cardiac hypertrophy. Phosphorylation of HDAC7 by the CaMK group member salt-inducible kinase 1 (SIK1) stabilized the deacetylase, leading to increased expression of c-Myc, which in turn stimulated a pathological gene program. These unexpected findings highlight the SIK1/HDAC7 signaling axis as a promising target for the treatment of cardiac hypertrophy and heart failure.
IIa 类组蛋白去乙酰化酶（HDACs）通过与促肥大转录因子（TF）肌细胞增强因子 2（MEF2）结合来抑制心肌细胞肥大。四个 IIa 类 HDACs - HDAC4、-5、-7 和 -9 - 可被钙/钙调蛋白依赖性蛋白激酶（CaMK）组的成员进行信号依赖性磷酸化。在应激反应中，HDAC4、HDAC5 和 HDAC9 在心肌细胞中经历磷酸化诱导的核输出，从而释放 MEF2 以刺激促生长基因；人们普遍认为 HDAC7 也是抗肥大的。然而，在本期 JCI 中，Hsu 及其同事表明，与其他 IIa 类 HDACs 形成鲜明对比的是，HDAC7 持续定位于心肌细胞质中，在那里促进心肌肥大。CaMK 组成员盐诱导激酶 1（SIK1）对 HDAC7 的磷酸化稳定了去乙酰化酶，导致 c-Myc 的表达增加，进而刺激了病理性基因程序。这些出人意料的发现突显了 SIK1/HDAC7 信号轴作为治疗心肌肥大和心力衰竭的有前途的靶点。
