ArticleHepatology (Baltimore, Md.)2025
Targeting protein hyper-SUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma cross talk.
Article in Hepatology (Baltimore, Md.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Development and Validation of a Crotonylation-Related Prognostic Risk Model for Cholangiocarcinoma Based on Integrative Transcriptome Analysis.Digestive diseases and sciences · 2026Article
- SUMOylation in cancer: molecular mechanisms and therapeutic implications.Molecular cancer · 2026Review
- Blockage of SUMO E1 enzyme inhibits ocular lens fibrosis by mediating SMAD4 SUMOylation.Genes & diseases · 2026Article
- Cholangiocarcinoma 2026: status quo, unmet needs and priorities.Nature reviews. Gastroenterology & hepatology · 2026Review
- Cancer-Associated Fibroblasts in Gastrointestinal Cancer Metastasis: Mechanisms and Emerging Therapeutic Strategies.Drug design, development and therapy · 2026Review
- ZNF184-mediated transcriptional activation of SAE1 drives the cell cycle entry and immune evasion in non-small cell lung cancer.Respiratory research · 2025Article
- Applications of 3D models in cholangiocarcinoma.Frontiers in oncology · 2025Review
- Machine Learning Modelling, Single-Cell Landscape Profiling and Spatial Transcriptomics Provide New Insights Into SUMOylation in Head and Neck Squamous Cell Carcinoma.IET systems biologyArticle
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26 authors.
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Abstract
BACKGROUND AND
aimsCholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target. APPROACH AND
resultsAnalysis of CCA tumors from 4 patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SUMO activating enzyme 1 ( SAE1 ) and the SUMO conjugating enzyme UBE2I , regardless of the tumor's molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and S-adenosyl-methionine) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts and increasing the recruitment of antitumor immune cells. In vitro, targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and S-adenosyl-methionine did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with cancer-associated fibroblasts revealed that depleting SUMOylation in CCA cells impaired cancer-associated fibroblast cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.
conclusionsAberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.
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