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USP14-mediated stabilization of ACTN1 maintains mesenchymal characteristics in glioblastoma
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USP14-mediated stabilization of ACTN1 maintains mesenchymal characteristics in glioblastoma
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Journal Article
USP14-mediated stabilization of ACTN1 maintains mesenchymal characteristics in glioblastoma
2025
Overview
Glioblastoma (GBM) is a highly aggressive primary brain tumor with a dismal prognosis, particularly in its mesenchymal (MES) subtype, which correlates strongly with poor survival. Despite this, the mechanisms preserving MES identity remain poorly understood. Here, we show that alpha-actinin 1 (ACTN1) is upregulated in MES GBM and drives proneural-to-mesenchymal transition (PMT). Using patient samples and multiple GBM cell lines, we find that ACTN1 overexpression promotes proliferation, invasion, and tumorigenesis, while its silencing diminishes these malignant traits and shifts gene expression away from MES markers. Mechanistically, we identify ubiquitin-specific peptidase 14 (USP14) as a pivotal deubiquitinase (DUB) that stabilizes ACTN1 by removing its ubiquitin chains. Pharmacological inhibition of USP14 with IU1 reduces ACTN1 protein levels, impairs MES-associated phenotypes, and suppresses tumor progression in vitro and in intracranial xenograft models. Clinically, elevated USP14 and ACTN1 expression correlates with poorer survival in GBM patients, highlighting the USP14–ACTN1 axis as a key driver of PMT and a promising therapeutic target for this devastating disease.
USP14 deubiquitinates and stabilizes ACTN1 to sustain the mesenchymal state of glioblastoma and drive tumor growth; clinically, elevated USP14/ACTN1 predicts poorer survival.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
