{"doi":"10.1093/nar/gkae547","title":"ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer","abstract":"Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.","journal":"Nucleic Acids Research","year":2024,"id":420099,"datarank":0.7025962119030966,"base_score":3.6109179126442243,"endowment":3.6109179126442243,"self_citation_contribution":0.5416376868966337,"citation_network_contribution":0.16095852500646285,"self_endowment_contribution":0.5416376868966337,"citer_contribution":0.16095852500646285,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":32,"citers_with_citation_signal":16,"citers_with_endowment":16,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE244025"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":314963,"name":"Qian Yang","orcid":"0000-0002-2405-2396","position":1,"is_corresponding":false},{"id":1210907,"name":"Mirja Rotinen","orcid":"0000-0002-0755-8360","position":2,"is_corresponding":false},{"id":1210908,"name":"Rongrong Huang","orcid":"0000-0002-9730-7898","position":3,"is_corresponding":false},{"id":1210909,"name":"Hyo‐Young Kim","orcid":"0000-0003-4427-3919","position":4,"is_corresponding":false},{"id":1176198,"name":"Brad Gallent","orcid":"0000-0001-7429-9779","position":5,"is_corresponding":false},{"id":249484,"name":"Yiwu Yan","orcid":"0000-0001-8289-7277","position":6,"is_corresponding":false},{"id":1211539,"name":"Radu M. 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