UBE2T-Mediated HP1α Ubiquitination Enhances Nucleolar Function and Promotes the Progression of IDH1/TP53-Mutant Glioma

作者：Fengqi Zhou, Yuanyuan Sun, Xinhua Chen, Di Wu, Zhennan Tao, Lingyun Wu, Gao Chen, Xiangyu Liu, Tianfu Yu · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-0261 · 被引用次数：4 · 研究领域：Ubiquitin and proteasome pathways、Glioma Diagnosis and Treatment、Protein Degradation and Inhibitors

PURPOSE: High-grade glioma is the most aggressive form of primary brain tumor, characterized by rapid progression and a grim prognosis. The presence of mutations in IDH1 and TP53 is associated with a specific molecular phenotype in glioma, and their interaction is a potential target for therapy. EXPERIMENTAL DESIGN: Our study utilized a combination of bioinformatics analysis, in vitro experiments, and in vivo tumor xenograft models to investigate the role of the ubiquitin-conjugating enzyme 2T (UBE2T) in the malignant progression of IDH1/TP53-mutant glioma. RESULTS: We found that UBE2T is overexpressed in the context of TP53 mutations and is linked to enhanced glioma cell proliferation and stemness. Mechanistically, UBE2T was shown to degrade HP1α via the ubiquitin-proteasome pathway, leading to the release of the suppressive effects of R-2-hydroxyglutarate on nucleolar function and an increase in rDNA transcription. The therapeutic potential of targeting UBE2T is underscored by the discovery that APR-246, a mutant p53 reactivator, effectively suppresses UBE2T expression and reverses the hyperactivity of nucleolar transcription. CONCLUSIONS: These findings suggest that UBE2T plays a crucial role in the progression of IDH1/TP53-mutant astrocytoma and that targeting UBE2T with APR-246 could be a promising therapeutic strategy for patients with these mutations. Our study provides a foundation for further research into the role of UBE2T in glioma and the development of targeted t...