ASC-J9®, and not Casodex or Enzalutamide, suppresses prostate cancer stem/progenitor cell invasion via altering the EZH2-STAT3 signals

• Our study provides one possible mechanism why the current ADT eventually fails to suppress prostate cancer (PCa) progression.
• ASC-J9®, but not Casodex or Ezalutamide, can suppress prostate cancer stem/progenitor cell invasion.
• This potential drug, ASC-J9®, suppresses PCa by killing differentiated PCa cells via EZH2-STAT3 signals and degrading AR.

Early studies suggested that prostate cancer (PCa) stem/progenitor (S/P) cells might play key roles to promote the tumor initiation and metastasis. Yet their linkage to the failure of androgen deprivation therapy (ADT), however, remains unclear. Here we demonstrated that the ADT with anti-androgens Casodex (also known as Bicalutamide) and Enzalutamide (also known as MDV3100), but not the newly identified AR degradation enhancer, ASC-J9®, increased PCa S/P population, which might then lead to enhance the PCa cell invasion. Targeting AR with ASC-J9®, and not targeting androgens with Casodex or Enzalutamide, led to suppress PCa S/P cell invasion. Mechanism dissection revealed ASC-J9® could suppress S/P cell invasion via altering the EZH2/STAT3 and/or AKT/EZH2/STAT3 signals. Together, these results suggest that targeting PCa S/P cells with ASC-J9® or inhibitors to interrupt the EZH2/STAT3 and/or Akt/EZH2/STAT3 signals may become a new therapy to overcome the unwanted side effects of Casodex or Enzalutamide to further suppress the PCa metastasis.