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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