Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1. Targeting Rac1 signaling by RNAi, expression of the dominant-negative Rac1 (Rac1 DN), or the specific Rac1 inhibitor NSC23766 greatly inhibits mutant p53 GOF in promoting tumor growth and metastasis. Furthermore, mutant p53 expression is associated with enhanced Rac1 activity in clinical tumor samples. These results uncover a new mechanism for Rac1 activation in tumors and, most importantly, reveal that activation of Rac1 is an unidentified and critical mechanism for mutant p53 GOF in tumorigenesis, which could be targeted for therapy in tumors containing mutant p53.
Bibliographical noteFunding Information:
This study was supported by National Institutes of Health (NIH) grants 1R01CA160558-01 and 1R01CA203965 and Department
of Defense grant W81XWH-16-1-0358 to W.H.; and NIH grant R01CA143204, the New Jersey Health Foundation, and Bush Medical Research Award to Z.F. X.Y. is supported by a New Jersey Commission on Cancer Research Post-doctoral Fellowship Award. Y.Z. is supported by NIH grant F99CA222734. W.H. and Z.F. designed experiments, analyzed the data, and wrote manuscript; X.Y., C.Z., Y.Z., J. Liu, A.W.L., M.N.B., and J. Li carried out the experiments and analyzed the data; and V.M.T., J.M.D., and L.L. carried out cancer sample data analysis.
- Gain of function
- Mutant p53