ArticleCell death & disease2024
E3 ubiquitin ligase UBR5 promotes gemcitabine resistance in pancreatic cancer by inducing O-GlcNAcylation-mediated EMT via destabilization of OGA.
Article in Cell death & disease, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- SIRT5-dependent desuccinylation licenses UBR5-mediated degradation of TAMM41 to regulate mitochondrial metabolism in lung adenocarcinoma.Biology direct · 2026Article
- Combining ferroptosis inducers with gemcitabine to enhance treatment efficacy in pancreatic cancer.Cancer & metabolism · 2026Article
- Decoding the regulatory code: O-GlcNAcylation in epithelial-mesenchymal transition (EMT).The Journal of biological chemistry · 2026Review
- IKBKE downregulation increases chemosensitivity through pyroptosis mediated by the caspase-3/GSDME pathway in pancreatic cancer.Journal of experimental & clinical cancer research : CR · 2026Article
- Targeting UAP1 with rabeprazole: a novel repurposed therapeutic strategy for multiple myeloma.Frontiers in pharmacology · 2026Article
- Post-Translational Modifications: Key "Regulators" of Pancreatic Cancer Malignant Phenotype-Advances in Mechanisms and Targeted Therapies.Biomedicines · 2025Review
- Understanding O-GlcNAc transferase (OGT): Every amino acid matters.The Journal of biological chemistry · 2025Review
- Ubiquitination in cancer: mechanisms and therapeutic opportunities.Cancer communications (London, England) · 2025Review
- A lactate-related tSNE signature defines prognostic subtypes of bladder cancer and reveals LINC01094-mediated VIM stabilization in metastasis and drug resistance.Frontiers in immunology · 2025Article
- Role of Ubiquitin-regulated EMT in Cancer Metastasis and Chemoresistance.International journal of biological sciences · 2025Review
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Authors and funding
9 authors.
Funding
Abstract
Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.
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