Sox4 Involved In The Dna Damage Response Of P53 Activation

DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. Tumor suppressor protein p53, the key component of DDR, is either lost or mutant in half of human tumors. SOX4 is aberrantly overexpressed in many tumors, however, its roles in tumorigenesis is still largely unknown.In this study, we first examined the effect of DNA damage on SOX4 expression in human cancer cells, and found SOX4 could be induced by several DNA damage agents in a p53-independent manner. Notalby, knockdown of SOX4 impairs p53 activatiokn in response to DNA damage by using Western blot, luciferase assays and ChIP assays. Furthermore, we demonstrated that SOX4 could interact with p53 in vitro and in vivo by GST pull-down and co-immunoprecipitation. Reciprocal mapping experiments showed that there're two independent regions in both SOX4 and p53 responsible for their interaction. Luciferase assays demonstrated that SOX4 specifically increased the transcriptional activity of p53, and the interaction is required for this effect. SOX4 stabilizes p53 protein through blocking Mdm2-mediated p53 ubiquitination, degradation and nuclear export via blocking the p53-Mdm2 interaction, thus prolonging the half-life of p53 protein. The significance of the activation of p53 by SOX4 lies in the fact that SOX4 promotes p53-dependent cell cycle arrest at G1 phase and apoptosis. In concert with these findings, SOX4 was found to inhibit tumor growth in a p53-dependent manner by soft agar assays and nude mice experiments.In conclusion, our findings shed light on the molecular mechanistic insight into the role of SOX4 in tumorigenesis as well as the complicated regulation network of p53 in response to DNA damage, and drugs targeting SOX4 may be a potential anti-cancer therapeutic approach for future studies.