UHRF1 regulates AR ubiquitination to promote the loss of AR signaling and enzalutamide resistance in progression of prostate cancer.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer, increasingly associated with loss of androgen receptor (AR) signaling, and in many cases induction of stemness phenotypes and neuroendocrine features. However, targeted therapies for this stage of the disease are currently lacking. In this study, we demonstrated the critical role of the epigenetic regulator UHRF1 in the enzalutamide resistance development of prostate cancer. We have shown that UHRF1 is highly expressed in enzalutamide-resistant prostate cancer cells and its expression correlates with the loss of AR-dependent glandular features. Knocking down UHRF1 led to increased AR expression and enhanced the activity of canonical AR signaling pathway in prostate cancer cells. The combination of UHRF1 knockdown with enzalutamide treatment demonstrated synergistic tumor inhibitory effects both in vitro and in vivo. Mechanistically, UHRF1 was found to bind to AR and promote its ubiquitination and degradation. Furthermore, inhibition of UHRF1 restored AR pathway activity and re-sensitized resistant prostate cancer cells to enzalutamide. Therefore, our findings elucidate an intracellular molecular mechanism that promotes prostate cancer lineage plasticity and suggest that UHRF1 may serve as a potential therapeutic target for overcoming resistance to AR-targeted therapies.