Cellular signalling · 2026
RUVBL1 supports TIP60-associated proteasome adaptation and temozolomide resistance in glioblastoma.
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Kong Yang, Zhu Wei, Xue Kun, Gao Ya, Ma Caifeng, Tang Shuo, Sun Wei, Cui Guangqiang, Tian Xinghan, Wang Haiying
Аннотация
BACKGROUND: Glioblastoma (GBM) remains highly lethal, and resistance to temozolomide (TMZ) is a major barrier to durable therapeutic response. Although MGMT-mediated DNA repair is a well-established mechanism of TMZ resistance, how GBM cells maintain proteostasis under sustained chemotherapy stress remains less defined.
METHODS: We analyzed RUVBL1 expression and clinical relevance in glioma datasets from TCGA and validation cohorts. Functional studies were performed using RUVBL1 knockdown, TMZ-resistant GBM cells, proteasome activity assays, protein aggregation analysis, ER stress assessment, and rescue experiments with wild-type or ATPase-deficient RUVBL1 constructs. The therapeutic effect of pharmacological RUVBL1/2 ATPase inhibition was evaluated using CB-6644 in combination with TMZ in vitro and in orthotopic xenograft models.
RESULTS: RUVBL1 was upregulated in gliomas and associated with higher tumor grade, aggressive molecular features, and poorer patient survival. In TMZ-resistant GBM cells, RUVBL1 supported elevated proteasome-related gene expression and proteasome activity. RUVBL1 knockdown impaired this adaptive proteostasis program, leading to protein aggregate accumulation, ubiquitinated protein buildup, ER stress activation, and enhanced TMZ-induced apoptosis. Mechanistically, RUVBL1 interacted with TIP60 and was associated with maintenance of H3K9/K27 acetylation, NRF1-related proteasome gene expression, and proteasome activity. Rescue experiments showed that wild-type RUVBL1, but not the ATPase-deficient D302N mutant, restored these effects, indicating the requirement of RUVBL1 ATPase activity. Pharmacological inhibition of the RUVBL1/2 ATPase complex by CB-6644 sensitized TMZ-resistant GBM cells to TMZ. In orthotopic xenograft models, CB-6644 combined with TMZ reduced tumor growth and extended survival without obvious systemic toxicity.
CONCLUSIONS: RUVBL1 contributes to TMZ resistance in GBM by supporting TIP60-associated proteasome adaptation and proteostasis maintenance under chemotherapy stress. Targeting the RUVBL1/2 ATPase complex may weaken this adaptive program and enhance TMZ efficacy, suggesting a proteostasis-related therapeutic vulnerability in TMZ-resistant GBM.
METHODS: We analyzed RUVBL1 expression and clinical relevance in glioma datasets from TCGA and validation cohorts. Functional studies were performed using RUVBL1 knockdown, TMZ-resistant GBM cells, proteasome activity assays, protein aggregation analysis, ER stress assessment, and rescue experiments with wild-type or ATPase-deficient RUVBL1 constructs. The therapeutic effect of pharmacological RUVBL1/2 ATPase inhibition was evaluated using CB-6644 in combination with TMZ in vitro and in orthotopic xenograft models.
RESULTS: RUVBL1 was upregulated in gliomas and associated with higher tumor grade, aggressive molecular features, and poorer patient survival. In TMZ-resistant GBM cells, RUVBL1 supported elevated proteasome-related gene expression and proteasome activity. RUVBL1 knockdown impaired this adaptive proteostasis program, leading to protein aggregate accumulation, ubiquitinated protein buildup, ER stress activation, and enhanced TMZ-induced apoptosis. Mechanistically, RUVBL1 interacted with TIP60 and was associated with maintenance of H3K9/K27 acetylation, NRF1-related proteasome gene expression, and proteasome activity. Rescue experiments showed that wild-type RUVBL1, but not the ATPase-deficient D302N mutant, restored these effects, indicating the requirement of RUVBL1 ATPase activity. Pharmacological inhibition of the RUVBL1/2 ATPase complex by CB-6644 sensitized TMZ-resistant GBM cells to TMZ. In orthotopic xenograft models, CB-6644 combined with TMZ reduced tumor growth and extended survival without obvious systemic toxicity.
CONCLUSIONS: RUVBL1 contributes to TMZ resistance in GBM by supporting TIP60-associated proteasome adaptation and proteostasis maintenance under chemotherapy stress. Targeting the RUVBL1/2 ATPase complex may weaken this adaptive program and enhance TMZ efficacy, suggesting a proteostasis-related therapeutic vulnerability in TMZ-resistant GBM.