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In prostate cancer (PCa), hypoxia is strongly associated with aggressive disease and poor prognosis. Hypoxia\u2010inducible factor (HIF) is the master transcriptional regulator mediating hypoxia adaptation and is mainly controlled through proteasomal degradation of its \u03b1\u2010subunit by the ubiquitin\u2013proteasome system (UPS). However, the contribution of deubiquitinases (DUBs) to HIF signalling in PCa remains largely unexplored. Using a computational strategy based on CA9 expression as a surrogate of HIF activity, we identified Ubiquitin\u2010Specific Protease 29 (USP29) as a key regulator associated with hypoxia and tumour progression and severity in PCa. Mechanistically, USP29 functions as a noncanonical positive regulator of HIF\u2010\u03b1 stability in a catalytic\u2010dependent manner. USP29 interacts with HIF\u20101\u03b1, reduces its poly\u2010ubiquitination and protects it from proteasomal degradation across multiple cancer cell lines. Additionally, USP29 stabilizes HIF\u20102\u03b1 acting on the C\u2010terminal region of HIF\u2010\u03b1. These findings uncover a novel regulatory layer of HIF signalling and highlight USP29 as a potential therapeutic target in hypoxia\u2010driven PCa progression.<\/jats:p>","DOI":"10.1002\/1878-0261.70268","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T09:48:19Z","timestamp":1778665699000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>USP29<\/scp>\n                    \u2010regulated noncanonical stabilization of the hypoxia\u2010inducible factor\u2010\u03b1 in aggressive prostate cancer"],"prefix":"10.1002","author":[{"given":"Amelie S","family":"Schober","sequence":"first","affiliation":[{"name":"Centro de Investigaci\u00f3n Cooperativa en Biociencias CIC bioGUNE, Basque Research and Technology Alliance (BRTA) Parque Tecnol\u00f3gico de Bizkaia\u2010Ed.801A  Derio Spain"},{"name":"Institute of Integrative Biology, Department of Biochemistry, Centre for Cell Imaging 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