USP33 deubiquitinates and stabilizes HIF‐2alpha to promote hypoxia response in glioma stem cells.

Hypoxia regulates tumor angiogenesis, metabolism, and therapeutic response in malignant cancers including glioblastoma, the most lethal primary brain tumor. The regulation of HIF transcriptional factors by the ubiquitin–proteasome system is critical in the hypoxia response, but hypoxia‐inducible deubiquitinases that counteract the ubiquitination remain poorly defined. While the activation of ERK1/2 also plays an important role in hypoxia response, the relationship between ERK1/2 activation and HIF regulation remains elusive. Here, we identified USP33 as essential deubiquitinase that stabilizes HIF‐2alpha protein in an ERK1/2‐dependent manner to promote hypoxia response in cancer cells. USP33 is preferentially induced in glioma stem cells by hypoxia and interacts with HIF‐2alpha, leading to its stabilization through deubiquitination. The activation of ERK1/2 upon hypoxia promoted HIF‐2alpha phosphorylation, enhancing its interaction with USP33. Silencing of USP33 disrupted glioma stem cells maintenance, reduced tumor vascularization, and inhibited glioblastoma growth. Our findings highlight USP33 as an essential regulator of hypoxia response in cancer stem cells, indicating a novel potential therapeutic target for brain tumor treatment. Synopsis: While hypoxia induced by tumor growth is recognized as a key selective pressure in solid cancers, the molecular mechanisms underlying control of HIF signaling remain unclear. This work identifies deubiquitinating enzyme USP33 as regulator of HIF‐2alpha in glioma, shedding new light on the complexities of brain tumor growth. Hypoxia induces deubiquitinase USP33 expression in glioma stem cells (GSCs).USP33 deubiquitinates and stabilizes HIF‐2alpha in GSCs in response to hypoxia.ERK1/2‐mediated phosphorylation of S484 HIF‐2alpha enhances binding to USP33.Depletion of USP33 impairs GSC maintenance and tumor sphere formation in vitro as well as glioblastoma growth in mice. [ABSTRACT FROM AUTHOR]