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Ubiquitin-conjugating enzyme E2S decreases the sensitivity of glioblastoma cells to temozolomide by upregulating PGAM1 via the interaction with OTUB2

文献类型： 外文期刊

作者： Xu, Lin 1 ; Wang, Baoju 2 ; Gang, Zhenbo 1 ; Han, Zhibin 1 ; Wang, Aowen 1 ; Liu, Qi 3 ; Liu, Hongyang 4 ; Wei, Shilong 1 ; Lin, Zhiguo 1 ; Xie, Chuncheng 1 ; Hu, Li 1 ;

作者机构： 1.Harbin Med Univ, Affiliated Hosp 1, Dept Neurosurg, 23 Post St, Harbin 150001, Heilongjiang, Peoples R China

2.Harbin Med Univ, Affiliated Hosp 1, Dept Gynecol, Harbin 150001, Heilongjiang, Peoples R China

3.Harbin Med Univ, Affiliated Hosp 1, Dept Pathol, Harbin 150001, Heilongjiang, Peoples R China

4.Chinese Acad Agr Sci, Harbin Vet Res Inst, State Key Lab Vet Biotechnol, Harbin 150069, Heilongjiang, Peoples R China

关键词： GBM; TMZ; UBE2S; PGAM1; OTUB2

期刊名称：INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES （ 影响因子：8.5； 五年影响因子：8.7 ）

ISSN： 0141-8130

年卷期： 2025 年 302 卷

页码：

收录情况： SCI

摘要： Background: Glioblastoma (GBM) is an aggressive cancer with limited therapeutic options. Investigating the mechanisms underlying temozolomide (TMZ) resistance and enhancing its sensitivity remain critical for improving GBM treatment outcomes. Ubiquitin-conjugating enzyme E2S (UBE2S) has been implicated in various cancers; however, its role in TMZ resistance in GBM remains unclear. Methods: After UBE2S knockdown, cell viability, apoptosis, and DNA damage were measured in TMZ-treated GBM cells. Immunoprecipitation coupled with mass spectrometry was employed to identify a protein complex involving UBE2S and phosphoglycerate mutase 1 (PGAM1). Co-immunoprecipitation and ubiquitination assays were conducted to examine the interactions among UBE2S, PGAM1, and Otubain-2 (OTUB2). In vivo, a GBM mouse model was used to evaluate the impact of UBE2S knockdown on TMZ efficacy. Results: UBE2S was found to be overexpressed in GBM cells, where it interacts with PGAM1 and OTUB2 to inhibit PGAM1 degradation via K48-linked deubiquitylation. This interaction increased PGAM1 protein levels, promoting DNA repair and reducing apoptosis, thereby decreasing the sensitivity of GBM cells to TMZ. Conclusion: UBE2S plays a critical role in TMZ resistance by stabilizing PGAM1 protein levels through its interaction with OTUB2. Targeting UBE2S represents a promising therapeutic strategy to enhance TMZ efficacy and overcome chemotherapy resistance in GBM.

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