Centromere protein U mediates the ubiquitination and degradation of RPS3 to facilitate temozolomide resistance in glioblastoma

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates Pub Date : 2025-02-21 DOI:10.1016/j.drup.2025.101214

Jinmin Sun , Wenyu Zhao , Lei Zhang , Sicheng Wu , Senrui Xue , Haowei Cao , Biao Xu , Xinmiao Li , Nan Hu , Tao Jiang , Yixin Xu , Zhifei Wang , Chao Zhang , Jing Ren

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引用次数: 0

Abstract

Aims

Temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma (GBM) therapy; however, resistance to TMZ remains a major obstacle in GBM treatment. The aim of this study is to elucidate the mechanisms underlying TMZ resistance and explore how to enhance the sensitivity of GBM to TMZ.

Methods

GBM organoids were generated from patient samples, and organoid-based TMZ sensitivity testing was performed. Transcriptome sequencing was conducted on GBM organoids, which identified Centromere protein U (CENPU) as a novel key gene mediating TMZ resistance. Histopathological assessments were carried out using immunohistochemistry (IHC) and Hematoxylin and Eosin (HE) staining. Single-cell sequencing data were utilized to determine the functional states of CENPU in GBM cells. Intracranial and subcutaneous glioma mouse models were constructed to evaluate the effect of CENPU on TMZ sensitivity. The underlying mechanisms were further investigated using immunofluorescence, lentivirus transduction, co-immunoprecipitation, mass spectrometry, alkaline comet assay et al.

Results

CENPU was found to be highly expressed in TMZ-resistant GBM organoids and enhanced the TMZ resistance of GBM cells by promoting DNA damage repair. Its abnormal expression correlates with poor clinical outcomes in glioma patients. In vivo studies demonstrated that downregulation of CENPU enhances the sensitivity of GBM to TMZ. Correspondingly, rescue of CENPU expression reversed this effect on TMZ sensitivity in GBM cells. Mechanistically, CENPU cooperates with TRIM5α to promote the ubiquitination and degradation of RPS3 by inducing its polyubiquitination at the K214 residue. This process subsequently activates the ERK1/2 pathway and promotes the expression of E2F1 and RAD51. Consequently, the degradation of RPS3 and upregulation of RAD51 in GBM cells enhance DNA damage repair, thereby contributing to TMZ resistance.

Conclusion

Our study identified CENPU as a novel key gene mediating TMZ resistance and elucidated its molecular mechanisms, providing a new target to overcome TMZ resistance in GBM.

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来源期刊

Drug Resistance Updates 医学-药学

CiteScore

26.20

自引率

11.90%

发文量

审稿时长

29 days

期刊介绍： Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation. Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective. *Expert reviews in clinical and basic drug resistance research in oncology and infectious disease *Describes emerging technologies and therapies, particularly those that overcome drug resistance *Emphasises common themes in microbial and cancer research