Selective class II HDAC inhibitors impair myogenesis by modulating the stability and activity of HDAC-MEF2 complexes.
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 MC1568 shows 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.
Nebbioso
Angela
A
Dipartimento di Patologia Generale, Seconda Università di Napoli, Napoli, Italy.
Manzo
Fabio
F
Miceli
Marco
M
Conte
Mariarosaria
M
Manente
Lucrezia
L
Baldi
Alfonso
A
De Luca
Antonio
A
Rotili
Dante
D
Valente
Sergio
S
Mai
Antonello
A
Usiello
Alessandro
A
Gronemeyer
Hinrich
H
Altucci
Lucia
L
D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors; D051379:Mice; D008954:Models, Biological; D024510:Muscle Development / Q000187:drug effects*; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D012097:Repressor Proteins / Q000378:metabolism; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D012097:Repressor Proteins; D006655:Histone Deacetylases