Unlike the androgen-deprivation therapy (ADT) to either reduce the androgen biosynthesis (for example, Abiraterone) or to prevent binding of androgen to the androgen receptor (AR) (for example, Casodex or Enzalutamide), that may result in the decreasing the prostate cancer (PCa) cell growth yet may also increasing the PCa cell invasion, the recently identified AR degradation enhancer ASC-J9® may function via degrading the AR protein to simultaneously suppress the PCa cell proliferation and invasion. The details of this unique mechanism, however, remain unclear. Here we found that ASC-J9® could suppress PCa cell invasion via inducing the sumoylation of STAT3, thereby inhibiting the STAT3 phosphorylation that led to suppress the EMT-SNAIL2 signals in both PCa DU145 and PC3 AR-negative cells. Mutation of lysine-679 on the sumoylation site of the STAT3 effectively blocked the ASC-J9®-suppressed PCa cell invasion in both in vitro cell lines and in vivo mouse models. These results suggest that in addition to degrading AR to suppress PCa cell proliferation, ASC-J9® can also function through an AR-independent mechanism via modulating the STAT3 sumoylation to alter the phospho-STAT3 status to suppress the PCa cell invasion. These dual functions of ASC-J9® to suppress PCa proliferation and invasion (via altering STAT3 sumoylation) may help us to develop a better anti-AR compound that may overcome the current antiandrogens' unwanted side of increasing the metastasis to better suppress the castration-resistant PCa progression.
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Cancer letters. 2018 Feb 06 [Epub ahead of print]
WanYing Lin, Jie Luo, Yin Sun, ChangYi Lin, Gonghui Li, Yuanjie Niu, Chawnshang Chang
George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA., George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology, The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY 14642, USA; Sex Hormone Research Center, China Medical University and Hospital, Taichung, 404, Taiwan, ROC. Electronic address: .