1. Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling
- Author
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Benoit G. Bruneau, Sarah McMahon, Nathanael S. Gray, Sarah A.B. Wood, Biao Wang, Qiming Duan, Yu Huang, Saptarsi M. Haldar, and Austin Hsu
- Subjects
0301 basic medicine ,Mef2 ,Immunology ,Cardiology ,Heart failure ,Protein Serine-Threonine Kinases ,Signal transduction ,Biology ,Cardiovascular ,Medical and Health Sciences ,Histone Deacetylases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,2.1 Biological and endogenous factors ,Myocytes, Cardiac ,Phosphorylation ,Aetiology ,Kinase activity ,Myocytes ,Ventricular Remodeling ,MEF2 Transcription Factors ,Kinase ,Effector ,HDAC7 ,General Medicine ,Protein-Serine-Threonine Kinases ,Cardiovascular disease ,Stem Cell Research ,medicine.disease ,Rats ,Cell biology ,Heart Disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,Muscle Biology ,Sprague-Dawley ,Cardiac ,Corepressor ,Research Article ,Signal Transduction - Abstract
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.
- Published
- 2020