Myocardin is known as an important transcriptional regulator in smooth and cardiac muscle development. Here we found that myocardin is frequently repressed during human malignant transformation, contributing to a differentiation defect. We demonstrate that myocardin is a transcriptional target of TGFβ required for TGFβ-mediated differentiation of human fibroblasts. Serum deprivation, intact contact inhibition response, and the p16ink4a/Rb pathway contribute to myocardin induction and differentiation. Restoration of myocardin expression in sarcoma cells results in differentiation and inhibition of malignant growth, whereas inactivation of myocardin in normal fibroblasts increases their proliferative potential. Myocardin expression is reduced in multiple types of human tumors. Collectively, our results demonstrate that myocardin is an important suppressive modifier of the malignant transformation process.
Bibliographical noteFunding Information:
The authors would like to thank Dr. Dina Ron for her helpful advice on in situ hybridization analysis. This research was supported by a Center of Excellence Grant from the Flight Attendant Medical Research Institute (FAMRI) and the Yad Abraham Center for Cancer Diagnosis and Therapy. V.R. is the incumbent of the Norman and Helen Asher Professorial Chair Cancer Research at the Weizmann Institute of Science.