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HDAC7 Sikens the Heart

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HDAC7 Sikens the Heart The black sheep of class IIa: HDAC7 SIKens the heart Joshua G. Travers, … , Tianjing Hu, Timothy A. McKinsey J Clin Invest. 2020;130(6):2811-2813. https://doi.org/10.1172/JCI137074. Commentary 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. Find the latest version: https://jci.me/137074/pdf The Journal of Clinical Investigation COMMENTARY The black sheep of class IIa: HDAC7 SIKens the heart Joshua G. Travers, Tianjing Hu, and Timothy A. McKinsey Division of Cardiology, Department of Medicine, and Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. repress gene expression, block cardiac hypertrophy by associating with the myo- Class IIa histone deacetylases (HDACs) repress cardiomyocyte hypertrophy cyte enhancer factor-2 (MEF2) transcrip- through association with the prohypertrophic transcription factor (TF) tion factor (TF) (11). myocyte enhancer factor-2 (MEF2). The four class IIa HDACs — HDAC4, -5, Although each of the four class IIa -7, and -9 — are subject to signal-dependent phosphorylation by members of HDACs contains conserved MEF2 binding 2+ the Ca /calmodulin-dependent protein kinase (CaMK) group. In response domains, initial work in cardiomyocytes to stress, HDAC4, HDAC5, and HDAC9 undergo phosphorylation-induced focused on HDAC5 and HDAC9. A model nuclear export in cardiomyocytes, freeing MEF2 to stimulate progrowth emerged in which HDAC5/9 are normally genes; it was generally assumed that HDAC7 is also antihypertrophic. bound to MEF2 in cardiomyocyte nuclei, However, in this issue of the JCI, Hsu and colleagues demonstrate that, in squelching expression of MEF2 target sharp contrast to the other class IIa HDACs, HDAC7 is constitutively localized genes that drive hypertrophy (11, 12). In to the cardiomyocyte cytoplasm, where it promotes cardiac hypertrophy. response to stress signals, HDAC5/9 are Phosphorylation of HDAC7 by the CaMK group member salt-inducible kinase phosphorylated on two serine residues, 1 (SIK1) stabilized the deacetylase, leading to increased expression of c-Myc, leading to association with the phos- which in turn stimulated a pathological gene program. These unexpected pho-serine binding protein 14-3-3 and findings highlight the SIK1/HDAC7 signaling axis as a promising target for subsequent nuclear export, freeing MEF2 the treatment of cardiac hypertrophy and heart failure. to stimulate prohypertrophic gene expres- sion. HDAC4 also represses MEF2 and cardiac hypertrophy and undergoes phos- phorylation-dependent nuclear export in cardiomyocytes (13). Kinases belonging to Cardiac hypertrophy and HF with cardiovascular disease (3–5), and in the calmodulin-dependent protein kinase Approximately six million Americans suf- animal models of pressure overload, inhi- (CaMK) group, including CaMKII, protein fer from heart failure (HF), placing an eco- bition of hypertrophy is beneficial rather kinase D (PKD), microtubule-associated nomic liability on the United States that than detrimental (6, 7). Thus, there is a kinase (MARK), and SIK, can effective- is projected to rise to approximately $70 need to elucidate molecular mechanisms ly phosphorylate the 14-3-3 target sites billion annually by 2030 (1). HF is asso- that control cardiomyocyte growth, with on class IIa HDACs (13–17). Remarkably, ciated with poor quality of life and a five- the goal of defining auspicious nodes for despite HDAC7 having a MEF2 binding year mortality rate nearing 50%, exceed- HF drug development (8). domain and the ability to undergo phos- ing that of many malignancies (2). HF is phorylation-dependent nuclear export, a a global problem that will likely become Class IIa HDACs as repressors possible role for this class IIa HDAC in the even more onerous given the ever-increas- of cardiac hypertrophy control of cardiac hypertrophy remained ing prevalence of risk factors such as aging Cardiac hypertrophy is associated with a unstudied during this 20-year span. and metabolic disease. stereotypical pattern of aberrant myocyte One hallmark of HF is cardiomyocyte gene expression (9, 10). A robust area of SIK1 promotes cardiac hypertrophy, a growth response driven by investigation over the last approximate- hypertrophy by stabilizing increased intracellular protein abundance ly 20 years has focused on how stress HDAC7 in the absence of cell division. Cardiac signals emanating from the cardiomyo- In this issue of the JCI, Hsu and colleagues hypertrophy has traditionally been viewed cyte cell surface transmit to the nucleus (18) demonstrated that HDAC7 actual- as a compensatory response that normal- to trigger this common gene program. ly stimulates cardiac hypertrophy. They izes wall stress and maximizes ventricular Insights into this process were uncovered began by investigating a previously unex- performance in the face of a pathogenic by the discovery that a subset of class IIa plored role for SIKs in the heart. Nonse- insult. However, chronic hypertrophy is histone deacetylases (HDACs), which lective pharmacological inhibitors of SIK associated with poor outcomes in patients are epigenetic regulators that typically catalytic activity blocked agonist-induced hypertrophy and reexpression of the fetal gene program in cultured neonatal rat ven- Related Article: p. 2966 tricular myocytes (NRVMs) and human cardiomyocytes derived from induced Conflict of interest: TAM received funding from Italfarmaco. Copyright: © 2020, American Society for Clinical Investigation. pluripotent stem cells. RNAi-mediated Reference information: J Clin Invest. 2020;130(6):2811–2813. https://doi.org/10.1172/JCI137074. knockdown of the three SIK family mem- jci.org Volume 130 Number 6 June 2020 2811 COMMENTARY The Journal of Clinical Investigation nist-mediated hypertrophy and fetal gene induction, while HDAC7 overexpression stimulated these processes. Mechanis- tically, as opposed to functioning in the nucleus to repress MEF2 transcriptional activity, HDAC7 is constitutively cytoplas- mic in NRVMs and appears to promote hypertrophy by enhancing expression of the c-Myc TF. Indeed, ectopic expres- sion of HDAC7 dramatically increased endogenous c-Myc protein expression and knockdown of c-Myc attenuated HDAC7- induced hypertrophy of NRVMs (18). Future considerations and clinical implications The most exciting discoveries in the lab are those that are unforeseen, and this one certainly fits the bill, opening up a pleth- ora of interesting questions and transla- tional angles. First, what is HDAC7 doing in the cytoplasm to promote c-Myc expres- sion? HDAC7 overexpression in cardiomy- ocytes profoundly increases c-Myc protein abundance, but only modestly augments c-Myc mRNA expression, suggesting that the deacetylase is targeting the TF through a posttranscriptional mechanism. c-Myc is predominantly a nuclear protein, and thus it is likely that HDAC7 indirectly enhances its expression. Given that c-Myc stability is tightly controlled by the ubiq- Figure 1. A model for regulation of cardiac hypertrophy by SIK1-dependent phosphorylation of uitin-proteasome system (UPS) (20), it is HDAC7. In response to stress signals, SIK1 phosphorylates HDAC7, leading to association with 14-3-3 protein and stabilization of the deacetylase. HDAC7 promotes c-Myc protein expression through an possible that HDAC7 regulates the local- undefined mechanism. c-Myc stimulates genes that drive cardiomyocyte hypertrophy. Dephosphor- ization or function of proteins that govern ylation of HDAC7 by a protein phosphatase (PPase) leads to ubiquitin-dependent (Ub-dependent) degradation of the TF. degradation of the deacetylase, thereby dampening this prohypertrophic signaling cascade. Is HDAC7 catalytic activity required to increase c-Myc expression in cardio- myocytes? Despite having conserved cat- bers revealed that SIK1 is prohypertro- ty that SIK1 stimulates cardiac hypertrophy alytic domains that have high affinity for phic. Consistent with this in vitro work, by targeting HDAC7. Surprisingly, HDAC7 acetyl-lysine, class IIa HDACs are unable mice lacking SIK1 globally were protected abundance was substantially diminished to deacetylate histones, leading some to against cardiac hypertrophy induced by when SIK1 was absent or pharmacological- speculate that their deacetylase domains left ventricular pressure overload and also ly inhibited. Conversely, HDAC7 mRNA simply serve as acetyl-lysine readers (21). had reduced cardiac fibrosis and improved levels
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