{"doi":"10.1172/jci168649","title":"Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs","abstract":"One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.","journal":"Journal of Clinical Investigation","year":2024,"id":419352,"datarank":0.5676284450877392,"base_score":3.784189633918261,"endowment":3.784189633918261,"self_citation_contribution":0.5676284450877392,"citation_network_contribution":0.0,"self_endowment_contribution":0.5676284450877392,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":43,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9579,"is_data_producer":false,"deposit_databanks":null,"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":763335,"name":"Maryam Labaf","orcid":"0000-0002-1215-0618","position":1,"is_corresponding":false},{"id":249849,"name":"Yawei Zhao","orcid":"0000-0002-1689-5406","position":2,"is_corresponding":false},{"id":1182593,"name":"Jude Owiredu","orcid":"0000-0002-7361-501X","position":3,"is_corresponding":false},{"id":906806,"name":"Songqi Zhang","orcid":"0000-0002-8719-376X","position":4,"is_corresponding":false},{"id":785999,"name":"Krishna Patel","orcid":"0009-0009-7963-0518","position":5,"is_corresponding":false},{"id":1076997,"name":"Kavita Venkataramani","orcid":"0000-0002-4007-2901","position":6,"is_corresponding":false},{"id":1182594,"name":"Jocelyn S. 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