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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Hui Huang,
  • Kaixiang Ni,
  • Chenhua Li,
  • Maorong Cai,
  • Yuankun Liu,
  • Jiahao Zhang,
  • Yifan Shen,
  • Yuning Chen,
  • Jun Sun,
  • Junfei Shao,
  • Yi Liu,
  • Wei Ji,
  • Jiantong Jiao

摘要

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.