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

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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. 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. 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. 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. Fig. 8 • UBE2S is identified as a key regulator of TMZ resistance in GBM cells. • UBE2S interacts with PGAM1 and OTUB2, promoting PGAM1 stabilization by inhibiting its K48-linked ubiquitination. • PGAM1 upregulation reduces DNA damage and apoptosis, contributing to decreased TMZ sensitivity in GBM cells. • UBE2S knockdown enhances TMZ efficacy in vitro and in vivo, significantly increasing DNA damage and apoptosis in GBM cells. • Targeting UBE2S represents a novel therapeutic strategy to overcome TMZ resistance and improve GBM treatment outcomes.