ArticleJournal of hepatology2021
Targeting UBC9-mediated protein hyper-SUMOylation in cystic cholangiocytes halts polycystic liver disease in experimental models.
Article in Journal of hepatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 24 citations in OpenAlex.
- Targeting protein hyper-SUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma cross talk.Hepatology (Baltimore, Md.) · 2025Article
- Leukemia inhibitory factor promotes human cholangiopathies, and its inhibition improves cholestasis in Abcb4-/- mice.Hepatology communications · 2025Article
- Disruption of oocyte SUMOylation impacts critical regulatory processes during folliculogenesis in mice†.Biology of reproduction · 2025Article
- SUMOylation involved in malignant progression of multiple tumors and SENP5 may improve the chemotherapy sensitivity of hypoxic tumors.Frontiers in pharmacology · 2025Article
- Effects of Mixtures of Emerging Pollutants and Drugs on Modulation of Biomarkers Related to Toxicity, Oxidative Stress, and Cancer.Metabolites · 2024Article
- Article
- Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.Orphanet journal of rare diseases · 2024Review
- New insights into SUMOylation and NEDDylation in fibrosis.Frontiers in pharmacology · 2024Review
- Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum.Genes · 2023Article
- Genetics, pathobiology and therapeutic opportunities of polycystic liver disease.Nature reviews. Gastroenterology & hepatology · 2022Review
- Polycystic Liver Disease: Advances in Understanding and Treatment.Annual review of pathology · 2022Review
- Article
- CPAP enhances and maintains chronic inflammation in hepatocytes to promote hepatocarcinogenesis.Cell death & disease · 2021Article
- Inhibition of NAE-dependent protein hyper-NEDDylation in cystic cholangiocytes halts cystogenesis in experimental models of polycystic liver disease.United European gastroenterology journal · 2021Article
- Scoping Review on Polycystic Liver Disease in PKD1/PKD2 Gene Carriers: Genetic Aspects, Pathophysiology, and Therapeutic Approaches.Journal of clinical and experimental hepatologyReview
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Authors and funding
16 authors at 6 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsPolycystic liver diseases (PLDs) are genetic disorders characterized by progressive development of multiple fluid-filled biliary cysts. Most PLD-causative genes participate in protein biogenesis and/or transport. Post-translational modifications (PTMs) are implicated in protein stability, localization and activity, contributing to human pathobiology; however, their role in PLD is unknown. Herein, we aimed to unveil the role of protein SUMOylation in PLD and its potential therapeutic targeting.
methodsLevels and functional effects of SUMOylation, along with response to S-adenosylmethionine (SAMe, inhibitor of the SUMOylation enzyme UBC9) and/or short-hairpin RNAs (shRNAs) against UBE2I (UBC9), were evaluated in vitro, in vivo and/or in patients with PLD. SUMOylated proteins were determined by immunoprecipitation and proteomic analyses by mass spectrometry.
resultsMost SUMOylation-related genes were found overexpressed (mRNA) in polycystic human and rat liver tissue, as well as in cystic cholangiocytes in culture compared to controls. Increased SUMOylated protein levels were also observed in cystic human cholangiocytes in culture, which decreased after SAMe administration. Chronic treatment of polycystic (PCK: Pkdh1-mut) rats with SAMe halted hepatic cystogenesis and fibrosis, and reduced liver/body weight ratio and liver volume. In vitro, both SAMe and shRNA-mediated UBE2I knockdown increased apoptosis and reduced cell proliferation of cystic cholangiocytes. High-throughput proteomic analysis of SUMO1-immunoprecipitated proteins in cystic cholangiocytes identified candidates involved in protein biogenesis, ciliogenesis and proteasome degradation. Accordingly, SAMe hampered proteasome hyperactivity in cystic cholangiocytes, leading to activation of the unfolded protein response and stress-related apoptosis.
conclusionsCystic cholangiocytes exhibit increased SUMOylation of proteins involved in cell survival and proliferation, thus promoting hepatic cystogenesis. Inhibition of protein SUMOylation with SAMe halts PLD, representing a novel therapeutic strategy. LAY SUMMARY: Protein SUMOylation is a dynamic post-translational event implicated in numerous cellular processes. This study revealed dysregulated protein SUMOylation in polycystic liver disease, which promotes hepatic cystogenesis. Administration of S-adenosylmethionine (SAMe), a natural UBC9-dependent SUMOylation inhibitor, halted polycystic liver disease in experimental models, thus representing a potential therapeutic agent for patients.
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