biostudies-literatureYoshihama YHHS | National Institutes of HealthUT | University of Texas MD Anderson Cancer CenterProstate Cancer Foundatione2026324118https://www.ebi.ac.uk/biostudies/studies/S-EPMC8433584biostudies-literatureUnknown118(36)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 ARProceedings of the National Academy of Sciences of the United States of AmericaAR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase.PMC8433584R01 CA231349-01A1R35 GM13011917CHAL17Prostate Cancer Moon ShotLi JWang YALaBella KAYoshihama YKim EWu CJHart TColic MShang XDePinho RASpring DJBertolet LfalseAR-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 AR2021-01-01T00:00:00Z2021 Sep2025-04-05T14:05:21.447Z2025-04-05T14:05:21.447ZS-EPMC84335843447520510.1073/pnas.2026324118