2. Academic Validation
  3. The E3 ubiquitin ligase STUB1 inhibits glioblastoma progression though promoting IKKα ubiquitination and blocking NF-κB signaling pathway

The E3 ubiquitin ligase STUB1 inhibits glioblastoma progression though promoting IKKα ubiquitination and blocking NF-κB signaling pathway

  • Int J Biol Macromol. 2025 Sep;321(Pt 2):146064. doi: 10.1016/j.ijbiomac.2025.146064.
Dong Zhang 1,  Shitong Chen 1,  Wen Peng 1,  Gexi Liu 1,  Qinghao Zhang 1,  Muhammad Usman Ghani 1,  Pengzi Zhou 1,  Hui Zhao 2,  Ping Liang 3,  Hongjuan Cui 4
Affiliations

Affiliations

  • 1 Cancer Center, Medical Research Institute, State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; Jinfeng Laboratory, Chongqing 401329, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China.
  • 2 Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR 999077, China.
  • 3 Department of Neurosurgery, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, 400014 Chongqing, China. Electronic address: liangping868@sina.com.
  • 4 Cancer Center, Medical Research Institute, State Key Laboratory of Resource Insects, Southwest University, Chongqing 400716, China; Jinfeng Laboratory, Chongqing 401329, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China. Electronic address: hcui@swu.edu.cn.
PMID: 40675300 DOI: 10.1016/j.ijbiomac.2025.146064
Abstract

Glioblastoma multiforme (GBM) is a highly aggressive malignant tumor with poor prognosis, high recurrence, and resistance to standard treatments, posing a significant therapeutic challenge. STUB1 (STIP1 Homology and U-box Containing Protein 1), also known as CHIP (C-terminus of HSC70-Interacting Protein), is a widely expressed E3 ubiquitin Ligase found in eukaryotes, previously known as a tumor suppressor, has been shown to inhibit the proliferation, invasion, and tumorigenesis of GBM cells. The mechanism by which STUB1 regulates IKKα-mediated NF-κB signaling in the classical NF-κB signaling pathway remains unexplored. Our study found that STUB1 interacts with the serine/threonine kinase domain of IKKα and is negatively correlated with it in glioblastoma. Furthermore, we demonstrated that STUB1 promotes the degradation of IKKα protein by facilitating polyubiquitination at the K296R site of the K48 linkage. Additionally, we showed that STUB1 inhibits inflammation and Cancer development by inhibiting IKKα expression, preventing the phosphorylation and degradation of IκBα, and consequently blocking NF-κB-P65 translocation to the nucleus and activation of target gene expression. In conclusion, our results suggest that STUB1 inhibits the malignant progression of glioblastoma through the STUB1-IKKα-P65 axis, which could serve as a potential therapeutic target to improve the prognosis and survival of GBM patients.

Keywords

Nuclear translocation; STUB1; Ubiquitination.

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