ADT increases prostate cancer cell invasion via altering AR/SALL4/SOX2-OCT4 stem cell signaling.

Abstract

Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients' survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression.