Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC–MEF2 complexes

Abstract

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.Histone deacetylase (HDAC) inhibitors are promising new epi-drugs, but the presence of both class I and class II enzymes in HDAC complexes precludes a detailed elucidation of the individual HDAC functions. By using the class II-specific HDAC inhibitor MC1568, we separated class I-and class II-dependent effects and defined the roles of class II enzymes in muscle differentiation in cultured cells and in vivo. MC1568 arrests myogenesis by (i) decreasing myocyte enhancer factor 2D (MEF2D) expression, (ii) by stabilizing the HDAC4-HDAC3-MEF2D complex, and (iii) paradoxically, by inhibiting differentiation-induced MEF2D acetylation. In vivo MC1568shows an apparent tissue-selective HDAC inhibition. In skeletal muscle and heart, MC1568 inhibits the activity of HDAC4 and HDAC5 without affecting HDAC3 activity, thereby leaving MEF2-HDAC complexes in a repressed state. Our results suggest that HDAC class II-selective inhibitors might have a therapeutic potential for the treatment of muscle and heart diseases.

Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

“…This suggests that inhibition of class I HDACs is sufficient to exert most of the beneficial effects observed in HDACi-treated mdx mice, once again emphasizing the key contribution to mdx pathogenesis by class I HDACs. Consistently, class II HDAC specific inhibitors have shown an opposite effect in vitro, inhibiting rather than promoting skeletal myogenesis (71).…”

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

“…Earlier studies have shown that it induces the reactivation of virus in neurons harboring latent virus (25). pyridin-3-ylmethyl 4-(2-aminophenylcarbamoyl)benzylcarbamate (MS275) and 3-[5-(3-(3-Fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC1568) at low concentrations act as specific inhibitors of HDAC 1 and 4, respectively (27,28). At high concentrations, their specificity decreases.…”

N ε -lysine acetylation determines dissociation from GAP junctions and lateralization of connexin 43 in normal and dystrophic heart

“…Assays were carried out as previously reported (33). Briefly, under liquid nitrogen, each tissue was pulverized to a powder with a mortar and pestle, and proteins were extracted with Lysis buffer (50 mM Tris·HCl, pH 7.0, 150 mM NaCl, 0.15% Nonidet P-40, 10% glycerol, 1.5 mM MgCl2, 1 mM NaVO 4 , 1 mM NaF) with protease inhibitors (Sigma), 1 mM DTT, and 0.2 mM PMSF.…”