Non-canonical functions of UGT2B17 promote castrate-resistant prostate cancer progression

When prostate cancer (PCa) overcomes the androgen receptor (AR) target therapy and progresses to the castrate-resistant prostate cancer (CRPC) stage, it becomes curable. UDP glucuronosyltransferase 2B17 (UGT2B17) is the key enzyme determining androgen bioavailability to AR inside PCa cells. However, whether UGT2B17 promotes CRPC progression remains poorly understood. Here, we report that anti-AR therapy increases UGT2B17 protein stability. UGT2B17 is localized in both the cytoplasm and nucleus to exert multiple non-enzymatic functions. In the cytoplasm, UGT2B17 activates unfolded protein response (UPR) to counteract endoplasmic reticulum (ER) stress for cell survival. UGT2B17 can exert its nuclear functions by stimulating c-Src kinase to activate AR in the absence of androgens. The UGT2B17-Src axis confers PCa cells resistant to DNA damage and promotes cell cycling by passing the G2 checkpoints through de-activating ATM and ATR kinases. We conclude that these non-enzymatic functions of UGT2B17 activate multiple survival pathways to allow CRPC progression.