Prostate cancer (PCa) is primarily driven by aberrant
Androgen Receptor (AR) signaling. Although there has been substantial advancement in
antiandrogen therapies, resistance to these treatments remains a significant obstacle, often marked by continuous or enhanced AR signaling in resistant
tumors. While the dysregulation of the ubiquitination-based protein degradation process is instrumental in the accumulation of oncogenic
proteins, including AR, the molecular mechanism of ubiquitination-driven AR degradation remains largely undefined. We identified UBE2J1 as the critical
E2 ubiquitin-conjugating enzyme responsible for guiding AR ubiquitination and eventual degradation. The absence of UBE2J1, found in 5-15% of PCa patients, results in disrupted AR ubiquitination and degradation. This disruption leads to an accumulation of AR
proteins, promoting resistance to
antiandrogen treatments. By employing a ubiquitination-based AR degrader to adeptly restore AR ubiquitination, we reestablished AR degradation and inhibited the proliferation of
antiandrogen-resistant PCa
tumors. These findings underscore the fundamental role of UBE2J1 in AR degradation and illuminate an uncharted mechanism through which PCa maintains heightened AR
protein levels, fostering resistance to
antiandrogen therapies.