{"doi":"10.1073/pnas.2026324118","title":"AR-negative prostate cancer is vulnerable to loss of JMJD1C demethylase","abstract":"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 (TNFα) signature, whereas combined loss of AR and JMJD1C strongly up-regulates the TNFα signature in human prostate cancer, suggesting TNFα signaling as a point of convergence for the combined actions of AR and JMJD1C. Correspondingly, AR-negative prostate cancer cells showed exquisite sensitivity to TNFα treatment and, conversely, TNFα 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 TNFα 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.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":182910,"datarank":0.40620753016533157,"base_score":2.70805020110221,"endowment":2.70805020110221,"self_citation_contribution":0.40620753016533157,"citation_network_contribution":0.0,"self_endowment_contribution":0.40620753016533157,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":299138,"name":"Kyle A. LaBella","orcid":"0000-0002-0473-9262","position":1,"is_corresponding":false},{"id":630022,"name":"Eiru Kim","orcid":"0000-0002-1901-5670","position":2,"is_corresponding":false},{"id":736618,"name":"Lori L. Bertolet","orcid":null,"position":3,"is_corresponding":false},{"id":80461,"name":"Medina Colic","orcid":"0000-0003-1442-1589","position":4,"is_corresponding":false},{"id":257598,"name":"Jiexi Li","orcid":"0000-0003-1508-5732","position":5,"is_corresponding":false},{"id":274885,"name":"Xiaoying Shang","orcid":"0009-0004-2398-4855","position":6,"is_corresponding":false},{"id":1884,"name":"Chang‐Jiun Wu","orcid":"0000-0001-8350-6397","position":7,"is_corresponding":false},{"id":243058,"name":"Denise J. Spring","orcid":"0000-0002-4593-0901","position":8,"is_corresponding":false},{"id":39929,"name":"Yanru Wang","orcid":"0000-0001-8272-2450","position":9,"is_corresponding":false},{"id":80465,"name":"Traver Hart","orcid":"0000-0002-1880-3341","position":10,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":11,"is_corresponding":false},{"id":735920,"name":"Yohei Yoshihama","orcid":"0000-0002-7634-8519","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:48:17.816498Z","pmid":"34475205","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}