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

Significance Prostate cancer is a major cause of cancer-related death in men. Emerging resistance to androgen receptor (AR) signaling inhibition therapy has heightened the need to identify therapeutic vulnerabilities specific to AR-negative prostate cancers. Analysis of CRISPR screen datasets in human prostate cancer cells identified high dependency for the histone demethylase JMJD1C across multiple AR-negative model systems. Integrated analyses revealed that combined AR and JMJD1C inactivation drives up-regulation of the TNFα network which provokes growth suppression. The exquisite sensitivity of AR-negative prostate cancer cells to JMJD1C inhibition may provide a therapeutic option for men with progressive castration-resistant prostate cancer.