AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase

Prostate cancer is a leading cause of cancer-related mortality in men. The widespread use of androgen receptor (AR) inhibitors has generated an increased incidence of AR-negative prostate cancer, triggering the need for effective therapies for such patients. Here, analysis of public genome-wide CRISPR screens in human prostate cancer cell lines identified histone demethylase JMJD1C (KDM3C) as an AR-negative context-specific vulnerability. Secondary validation studies in multiple cell lines and organoids, including isogenic models, confirmed that small hairpin RNA (shRNA)-mediated depletion of JMJD1C potently inhibited growth specifically in AR-negative prostate cancer cells. To explore the cooperative interactions of AR and JMJD1C, we performed comparative transcriptomics of 1) isogenic AR-positive versus AR-negative prostate cancer cells, 2) AR positive versus AR-negative prostate cancer tumors, and 3) isogenic JMJD1C-expressing versus JMJD1C-depleted AR-negative prostate cancer cells. Loss of AR or JMJD1C generates a modest tumor necrosis factor alpha (TNF alpha) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNF alpha signature in human prostate cancer, suggesting TNF alpha signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNF alpha treatment and, conversely, TNF alpha pathway inhibition via inhibition of its downstream effector MAP4K4 partially reversed the growth defect of JMJD1C-depleted AR-negative prostate cancer cells. Given the deleterious systemic side effects of TNF alpha therapy in humans and the viability of JMJD1C-knockout mice, the identification of JMJD1C inhibition as a specific vulnerability in AR-negative prostate cancer may provide an alternative drug target for prostate cancer patients progressing on AR inhibitor therapy.

Automated summary

Prostate cancer is a common cause of cancer deaths in men, especially when AR inhibitors are utilized. The study found that the histone demethylase JMJD1C plays a crucial role in AR-negative prostate cancer, with depletion inhibiting cell growth. Loss of AR or JMJD1C results in a modest TNF alpha signature, while combined loss leads to a significant up-regulation of TNF alpha, indicating TNF alpha signaling as a convergence point for AR and JMJD1C.