USP29‐regulated noncanonical stabilization of the hypoxia‐inducible factor‐α in aggressive prostate cancer
7 affiliations
- 1Centro de Investigación Cooperativa en Biociencias CIC bioGUNE, Basque Research and Technology Alliance (BRTA) Parque Tecnológico de Bizkaia‐Ed.801A Derio Spain
- 2Institute of Integrative Biology, Department of Biochemistry, Centre for Cell Imaging University of Liverpool UK
- 3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC) Madrid Spain
- 4Ikerbasque, Basque Foundation for Science Bilbao Bizkaia Spain
- 5Translational Prostate Cancer Research Lab, CIC bioGUNE‐Basurto Biocruces Bizkaia Research Health Institute Barakaldo Spain
- 6Department of Biochemistry and Molecular Biology University of the Basque Country (UPV/EHU) Leioa Bizkaia Spain
- 7Present address: CNRS UMR 5305, Tissue Biology and Therapeutic Engineering Laboratory (LBTI), Universite Claude Bernard Lyon1 France
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.
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BibTeX
@article{schober2026usp29regulated,
title = {{USP29‐regulated noncanonical stabilization of the hypoxia‐inducible factor‐α in aggressive prostate cancer}},
author = {Amelie S Schober and Leire Moreno‐Cugnon and Laura Martínez‐Pérez and Amaia Ercilla and Amaia Zabala‐Letona and Adrián Vicente‐Barrueco and Maider Fagoaga‐Eugui and Saioa Garcia‐Longarte and Blanca Calle‐Ciborro and Encarnación Pérez‐Andrés and Onintza Carlevaris and Sara Pozo and Isabel Mendizabal and Ugo Mayor and Arkaitz Carracedo and Violaine Sée and Edurne Berra},
journal = {Molecular Oncology},
year = {2026},
month = may,
doi = {10.1002/1878-0261.70268},
url = {https://doi.org/10.1002/1878-0261.70268},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - USP29‐regulated noncanonical stabilization of the hypoxia‐inducible factor‐α in aggressive prostate cancer
AU - Amelie S Schober
AU - Leire Moreno‐Cugnon
AU - Laura Martínez‐Pérez
AU - Amaia Ercilla
AU - Amaia Zabala‐Letona
AU - Adrián Vicente‐Barrueco
AU - Maider Fagoaga‐Eugui
AU - Saioa Garcia‐Longarte
AU - Blanca Calle‐Ciborro
AU - Encarnación Pérez‐Andrés
AU - Onintza Carlevaris
AU - Sara Pozo
AU - Isabel Mendizabal
AU - Ugo Mayor
AU - Arkaitz Carracedo
AU - Violaine Sée
AU - Edurne Berra
PY - 2026
DA - 2026/05/13
JO - Molecular Oncology
DO - 10.1002/1878-0261.70268
UR - https://doi.org/10.1002/1878-0261.70268
AB - 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.
SN - 1574-7891
SN - 1878-0261
ER -