Noncanonical functions of UGT2B17 promote castration-resistant prostate cancer progression.

Abstract

Androgen deprivation therapy is the primary treatment for advanced prostate tumors. While initially effective, tumor progression to the therapy-resistant stage is inevitable. Paradoxically, UDP glucuronosyltransferase family 2 member B17 (UGT2B17), the key enzyme responsible for androgen catabolism in prostate tumor cells, is upregulated in therapy-resistant tumors, though its role in tumor progression remains unclear. Here, we demonstrate that UGT2B17 possesses multiple oncogenic functions independent of androgen catabolism. It modulates protein-folding pathways, allowing tumor cells to endure therapy-induced stress. UGT2B17 also regulates transcription associated with cell division and the DNA damage response, enabling unchecked cell proliferation. Targeting the newly identified UGT2B17 functions using a combination of inhibitors reduced tumor growth in therapy-resistant tumor models, highlighting a promising therapeutic strategy. Collectively, these findings reveal a mechanism by which prostate tumors exploit UGT2B17 to evade therapy and highlight its potential as a therapeutic target in advanced prostate cancer.