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SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer

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  • Additional Information
    • Contributors:
      Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas = Biomedical Research Network Center for Liver and Digestive Diseases Madrid (CIBERehd); Center for Cooperative Research in Biosciences = Centro de Investigación cooperativa en biociencia (Derio, Biscay, Espagne) (CIC bioGUNE); Institut de signalisation, biologie du développement et cancer - Institute of Developmental Biology and Cancer (IBDC); Université Nice Sophia Antipolis (1965 - 2019) (UNS)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UniCA); Institut de pharmacologie et de biologie structurale (IPBS); Université Toulouse III - Paul Sabatier (UT3); Communauté d'universités et établissements de Toulouse (Comue de Toulouse)-Communauté d'universités et établissements de Toulouse (Comue de Toulouse)-Centre National de la Recherche Scientifique (CNRS); Institut des Technologies Avancées en sciences du Vivant (ITAV); Instituto de Investigaciones Químicas (IIQ); Consejo Superior de Investigaciones Cientificas España = Spanish National Research Council Spain (CSIC)-Universidad de Sevilla = University of Seville
    • Publication Information:
      CCSD
      Elsevier
    • Publication Date:
      2019
    • Collection:
      HAL Université Côte d'Azur
    • Abstract:
      International audience ; Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC).Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC.Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using site-directed mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors.Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its onco-genic role in liver cancer. und: This work was supported by grants from NIH (US Department of Health and Human services)-R01AR001576-11A1 (J.M.M and M.L.M-C.), Gobierno Vasco-Departamento de Salud 2013111114 (to M.L.M.-C), ELKARTEK 2016, Departamento de Industria del Gobierno Vasco (to M.L.M.-C), MINECO: SAF2017-87301-R and SAF2014-52097-R integrado ...
    • Relation:
      info:eu-repo/semantics/altIdentifier/pmid/30594553; PUBMED: 30594553; PUBMEDCENTRAL: PMC6412020
    • Accession Number:
      10.1016/j.ebiom.2018.12.031
    • Online Access:
      https://hal.science/hal-02351178
      https://hal.science/hal-02351178v1/document
      https://hal.science/hal-02351178v1/file/EBioMedicine%2040%20%282019%29%20406%E2%80%93421.pdf
      https://doi.org/10.1016/j.ebiom.2018.12.031
    • Rights:
      https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess
    • Accession Number:
      edsbas.758B7D26