c‐Ski activates MyoD in the nucleus of myoblastic cells through suppression of histone deacetylases

c‐Ski, originally identified as an oncogene product, induces myogenic differentiation in nonmyogenic fibroblasts through transcriptional activation of muscle regulatory factors. Although c‐Ski does not bind to DNA directly, it binds to DNA through interaction with Smad proteins and regulates signaling activities of transforming growth factor‐β (TGF‐β). In the present study, we show that c‐Ski activates the myogenin promoter independently of regulation of endogenous TGF‐β signaling. Expression of myogenin is regulated by a transcription factor complex containing proteins of the MyoD family and the myocyte enhancer factor 2 (MEF2) family. c‐Ski acts on the MyoD–MEF2 complex and modulates the activity of MyoD in myogenin promoter regulation. Interestingly, histone deacetylase (HDAC) inhibitors up‐regulated basal activity of transcription from a MyoD‐responsive reporter, although c‐Ski failed to further augment this transcription in the presence of HDAC inhibitors. c‐Ski is observed both in the cytoplasm and in the nucleus, but its nuclear localization is required for myogenic differentiation. We conclude that c‐Ski induces myogenic differentiation through acting on MyoD and inhibiting HDAC activity in the nucleus of myogenic cells.