Staufen1 controls mitochondrial metabolism via HIF2α in embryonal rhabdomyosarcoma and promotes tumorigenesis

Almasi, Shekoufeh, SarmastiEmami, Sahar, Baird, Stephen, Ning, Zhibin, Figeys, Daniel, Côté, Jocelyn, Cowan, Kyle N. and Jasmin, Bernard J. (2023) Staufen1 controls mitochondrial metabolism via HIF2α in embryonal rhabdomyosarcoma and promotes tumorigenesis. Cellular and Molecular Life Sciences, 80 (11). pp. 1-28. ISSN 1420-682X

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Abstract

Elevated mitochondrial metabolism promotes tumorigenesis of Embryonal Rhabdomyosarcomas (ERMS). Accordingly, targeting oxidative phosphorylation (OXPHOS) could represent a therapeutic strategy for ERMS. We previously demonstrated that genetic reduction of Staufen1 (STAU1) levels results in the inhibition of ERMS tumorigenicity. Here, we examined STAU1-mediated mechanisms in ERMS and focused on its potential involvement in regulating OXPHOS. We report the novel and differential role of STAU1 in mitochondrial metabolism in cancerous versus non-malignant skeletal muscle cells (NMSkMCs). Specifically, our data show that STAU1 depletion reduces OXPHOS and inhibits proliferation of ERMS cells. Our findings further reveal the binding of STAU1 to several OXPHOS mRNAs which affects their stability. Indeed, STAU1 depletion reduced the stability of OXPHOS mRNAs, causing inhibition of mitochondrial metabolism. In parallel, STAU1 depletion impacted negatively the HIF2α pathway which further modulates mitochondrial metabolism. Exogenous expression of HIF2α in STAU1-depleted cells reversed the mitochondrial inhibition and induced cell proliferation. However, opposite effects were observed in NMSkMCs. Altogether, these findings revealed the impact of STAU1 in the regulation of mitochondrial OXPHOS in cancer cells as well as its differential role in NMSkMCs. Overall, our results highlight the therapeutic potential of targeting STAU1 as a novel approach for inhibiting mitochondrial metabolism in ERMS.

Item Type:	Article
Additional Information:	We thank Dr. Pantic (University of Padua, Italy) for providing HSMM-C2 and HSMM-C3 cell lines. The online version contains supplementary material available at https://doi.org/10.1007/s00018-023-04969-4 The data underlying this article are available in the article and in its online supplementary material. “The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [28] partner repository with the dataset identifier PXD042156”.
Uncontrolled Keywords:	embryonal rhabdomyosarcoma,mitochondrial metabolism,oxphos,stau1,molecular medicine,molecular biology,pharmacology,cellular and molecular neuroscience,cell biology,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1300/1313
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Related URLs:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	09 Mar 2026 12:30
Last Modified:	15 Mar 2026 07:30
URI:	https://ueaeprints.uea.ac.uk/id/eprint/102267
DOI:	10.1007/s00018-023-04969-4

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