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

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.