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Updated: May 28, 2025
SUMO-Binding Entities SUBEs as Tools for the Enrichment, Isolation, Identification, and Characterization of the SUMO Proteome in Liver Cancer
Published on: November 1, 2019
Targeting protein hyper-SUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and
Paula Olaizola1,2,3, Irene Olaizola1, Marta Fernandez de Ara1
1Department of Liver and Gastrointestinal Diseases, Biogipuzkoa Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Donostia-San Sebastian, Spain.
Background And Aims:
Cholangiocarcinoma (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 Results:
Analysis 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.
Conclusions:
Aberrant 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.
Insights
Aberrant protein SUMOylation drives cholangiocarcinoma (CCA) progression. Targeting SUMOylation inhibits CCA growth and reshapes the tumor microenvironment, showing therapeutic potential for this deadly cancer.
Area of Science:
- Biochemistry and Molecular Biology
- Oncology
- Cancer Research
Background:
- Cholangiocarcinoma (CCA) is a group of aggressive biliary tract cancers with a poor prognosis.
- Disruptions in post-translational modifications, including SUMOylation, are implicated in cancer development.
- The specific role of SUMOylation in cholangiocarcinogenesis requires further investigation.
Purpose of the Study:
- To investigate the role of protein SUMOylation in the development and progression of cholangiocarcinoma.
- To explore the potential of targeting SUMOylation as a therapeutic strategy for CCA.
Main Methods:
- Analysis of SUMOylation machinery gene expression (SAE1, UBE2I) in CCA patient cohorts and cell lines.
- Identification of deregulated SUMOylated proteins using immunoprecipitation and mass spectrometry.
- Inhibition of SUMOylation using genetic (UBE2I knockdown) and pharmacological (ML792, S-adenosyl-methionine) approaches in preclinical CCA models.
Main Results:
- Increased expression of SAE1 and UBE2I, leading to elevated SUMO1-conjugated proteins, was observed in CCA.
- Higher SAE1 and UBE2I levels correlated with unfavorable clinical outcomes.
- SUMOylation inhibition suppressed tumor growth, reduced cancer-associated fibroblasts, increased anti-tumor immune cells, and induced CCA cell death, without affecting normal cholangiocytes.
Conclusions:
- Aberrant SUMOylation is a key driver of CCA progression, promoting cell survival, proliferation, and influencing the tumor microenvironment.
- Targeting SUMOylation effectively inhibits CCA growth in preclinical models.
- Inhibition of SUMOylation represents a promising therapeutic strategy for cholangiocarcinoma.
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