USP29 ‐regulated noncanonical stabilization of the hypoxia‐inducible factor‐α in aggressive prostate cancer

Abstract

Oxygen availability is frequently compromised in solid tumours, making intratumoural hypoxia a common feature of cancer. In prostate cancer (PCa), hypoxia is strongly associated with aggressive disease and poor prognosis. Hypoxia‐inducible factor (HIF) is the master transcriptional regulator mediating hypoxia adaptation and is mainly controlled through proteasomal degradation of its α‐subunit by the ubiquitin–proteasome 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‐Specific 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‐α stability in a catalytic‐dependent manner. USP29 interacts with HIF‐1α, reduces its poly‐ubiquitination and protects it from proteasomal degradation across multiple cancer cell lines. Additionally, USP29 stabilizes HIF‐2α acting on the C‐terminal region of HIF‐α. These findings uncover a novel regulatory layer of HIF signalling and highlight USP29 as a potential therapeutic target in hypoxia‐driven PCa progression.