Host: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
Name : WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
Location : Kyoto
Date : July 01, 2018 - July 06, 2018
Sumoylation, the conjugation of a small ubiquitin-like modifier (SUMO) protein to a target, has diverse cellular effects. However, the functional roles of SUMO modification during myogenesis have not been fully elucidated. Here we report that basal sumoylation of histone deacetylase 1 (HDAC1) enhances the deacetylation of MyoD in undifferentiated myoblasts, whereas further sumoylation of HDAC1 contributes to switching the binding partner from MyoD to Rb to induce myocyte differentiation. Differentiation in C2C12 skeletal myoblasts induced new immunoblot bands above HDAC1 that were gradually enhanced during differentiation. Using SUMO inhibitors and sumoylation assays, we showed that the upper band was caused by sumoylation of HDAC1 during differentiation. Basal deacetylase activity was not altered in mutant HDAC1 K444/476R (HDAC1 2R) that was resistant to SUMO modification. Either differentiation or transfection of SUMO1 increased HDAC1 activity, which was attenuated in HDAC1 2R. Furthermore, HDAC1 2R failed to deacetylate MyoD. Binding of HDAC1 to MyoD was attenuated by K444/476R. Binding of HDAC1 to MyoD was gradually reduced after 2 days of differentiation. Transfection of SUMO1 induced dissociation of HDAC1 from MyoD, whereas it potentiated its binding to Rb. SUMO1-transfection further attenuated HDAC1-induced inhibition of MCK luciferase activity, which was reversed in HDAC1 2R. HDAC1 2R failed to inhibit myogenesis as well as muscle gene expression. In conclusion, HDAC1 sumoylation has a dual role in MyoD signaling: enhancement of HDAC1 deacetylation of MyoD in the basally sumoylated state of undifferentiated myoblasts and dissociation of HDAC1 from MyoD during myogenesis.
