2. Academic Validation
  3. TRIM25 promotes glioblastoma progression by stabilizing HIF-1α expression in normoxia through K11/K29 polyubiquitination

TRIM25 promotes glioblastoma progression by stabilizing HIF-1α expression in normoxia through K11/K29 polyubiquitination

  • Cell Death Dis. 2026 Apr 22;17(1):530. doi: 10.1038/s41419-026-08757-3.
Hui Huang # 1,  Kaixiang Ni # 2 3,  Chenhua Li # 1,  Maorong Cai # 1,  Yuankun Liu 1,  Jiahao Zhang 1,  Yifan Shen 1,  Yuning Chen 1,  Jun Sun 4,  Junfei Shao 5,  Yi Liu 6 7,  Wei Ji 8,  Jiantong Jiao 9
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China.
  • 2 Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada.
  • 3 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
  • 4 Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 5 Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 6 Ottawa Hospital Research Institute, Regenerative Medicine Program, Ottawa, ON, Canada. [email protected].
  • 7 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada. [email protected].
  • 8 Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • 9 Department of Neurosurgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 42020378 DOI: 10.1038/s41419-026-08757-3
Abstract

Glioblastoma (GBM) frequently activates hypoxia signaling even under normoxic conditions, yet the mechanism sustaining hypoxia-inducible factor-1α (HIF-1α) stability remains unclear. Here, we identify the E3 ubiquitin Ligase TRIM25 as a key driver of this phenomenon. TRIM25, aberrantly upregulated in GBM, directly binds HIF-1α and catalyzes K11/K29-linked polyubiquitination at lysine 532 of hydroxylated HIF-1α, preventing its canonical proteasomal degradation. This non-canonical ubiquitin modification stabilizes HIF-1α despite normal oxygen availability and sustains a pseudohypoxic transcriptional program in GBM cells. Functional studies in GBM cell lines, patient-derived cultures, and tumor models demonstrate that TRIM25-mediated HIF-1α stabilization promotes tumor proliferation, invasion, and angiogenic potential. Importantly, small-molecule screening identified T7117 as an inhibitor that disrupts the TRIM25-HIF-1α interaction, suppresses tumor growth, and enhances temozolomide efficacy. Together, our findings uncover a previously unrecognized ubiquitin mechanism that stabilizes hydroxylated HIF-1α under normoxia, revealing the TRIM25-HIF-1α axis as a driver of GBM pseudohypoxia and a potential therapeutic target.

Figures
Products