Post-transcriptional control of HIF-1α by MBNL1 restrains hypoxia-driven stemness in GBM
MBNL1 binds the HIF-1α 3'UTR to promote rapid mRNA decay, thereby limiting HIF-1 activity and hypoxia-induced stemness in glioblastoma. Using patient-derived glioma stem cells, we show that MBNL1 loss stabilizes HIF-1α mRNA and increases HIF-1α protein, HRE reporter activity, and target gene expression under hypoxia; MBNL1 knockout also prolongs target gene expression after reoxygenation, indicating enhanced hypoxia "memory." MBNL1 depletion markedly elevates stemness markers (KLF4, SOX2, GLI1) and clonogenic growth, and re-expression of MBNL1 reverses these effects. These results identify a post-transcriptional MBNL1-HIF1α axis that controls hypoxia signaling and stemness, with implications for GBM therapy.
Authors
- Gerald M. Wilson (ORCID: https://orcid.org/0000-0002-1273-7507)
- Eli E. Bar (ORCID: https://orcid.org/0000-0003-4561-4631)
- Ian Mills (ORCID: https://orcid.org/0000-0003-1334-2686)
- L. Åkerman
- Chixiang Chen (ORCID: https://orcid.org/0000-0001-5474-2833)
- Jeffrey A. Winkles (ORCID: https://orcid.org/0000-0002-3305-1424)
- Xiaoxuan Fan (ORCID: https://orcid.org/0000-0003-0501-771X)
- Haoyu Ren (ORCID: https://orcid.org/0000-0003-3410-3051)
- Fahim Ahmad (ORCID: https://orcid.org/0000-0002-7216-5539)
- Nina C. Lee
- Graeme F. Woodworth (ORCID: https://orcid.org/0000-0001-9663-0768)
- Blair P. Rendina
Institutions
- University of Maryland, Baltimore (US)
- University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center
- University of Maryland, Baltimore County (US)
Publication Details
- Journal
- Neoplasia
- Published
- 2025-12-08
- DOI
- https://doi.org/10.1016/j.neo.2025.101262
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00