Smad7-Skp2 complex orchestrates c-Myc stability, impacting on the cytostatic effect of TGF-β

Abstract

In most of human cancer, the c-Myc proto-oncogene is highly activated. Dysregulation of c-Myc oncoprotein contributes to drive tumorigenesis in numerous tissues and organs. Thus, targeting c-Myc stability can be a critical step for cancer therapy. Here we report Smad7 as a key molecule to regulate c-Myc stability and activity by recruiting F-box protein, Skp2. Ectopic expression of Smad7 down-regulated the protein level of c-Myc without affecting transcription level and significantly repressed its transcriptional activity, leading to inhibition of cell proliferation and tumorigenic activity. Furthermore, Smad7 enhanced ubiquitination of c-Myc through direct interaction with c-Myc and recruitment of Skp2. Ablation of Smad7 resulted in less sensitivity to the growth inhibitory effect of TGF-β by inducing stable c-Myc expression. In conclusion, these findings that Smad7 functions as a transductory role in c-Myc oncoprotein degradation and enhances the cytostatic effect of TGF-β signaling provide new insightful therapeutic approach for cancer treatment.