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Here, we identify the HIF1\u03b1-PHD1-FOXA1 axis as a critical mediator of hypoxic adaptation and androgen signaling suppression. Using genome-wide profiling, we demonstrate that hypoxia reprograms HIF1\u03b1 chromatin occupancy, shifting its cooperation from AR to FOXA1. Mechanistically, HIF1\u03b1 physically interacts with FOXA1, destabilizing it via PHD1-mediated hydroxylation\u2014a previously unrecognized post-translational regulatory node. Under hypoxia, loss of FOXA1 attenuates androgen-responsive transcription while activating hypoxia-inducible genes, demonstrating a dual role for this axis in hypoxia adaptation and prostate cancer progression. Genetic or pharmacological disruption of HIF1\u03b1-PHD1-FOXA1 impairs prostate cancer proliferation and migration, underscoring its translational relevance. Our findings establish oxygen-dependent FOXA1 degradation as a linchpin connecting microenvironmental stress to transcriptional plasticity in advanced prostate cancer, offering new therapeutic avenues.<\/jats:p>","DOI":"10.3390\/cells14131008","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T04:11:04Z","timestamp":1751429464000},"page":"1008","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["HIF1\u03b1-PHD1-FOXA1 Axis Orchestrates Hypoxic Reprogramming and Androgen Signaling Suppression in Prostate Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Limiao","family":"Liang","sequence":"first","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dandan","family":"Dong","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxue","family":"Sun","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3467-4241","authenticated-orcid":false,"given":"Qin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland"},{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiayun","family":"Yang","sequence":"additional","affiliation":[{"name":"Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6546-9334","authenticated-orcid":false,"given":"Gong-Hong","family":"Wei","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China"},{"name":"Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, 90220 Oulu, Finland"},{"name":"State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6389-7404","authenticated-orcid":false,"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University Shanghai Cancer Center, Shanghai Medical College of Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J. 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