Dokumentenart: | Artikel | ||||
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Titel eines Journals oder einer Zeitschrift: | EBioMedicine | ||||
Verlag: | ELSEVIER SCIENCE BV | ||||
Ort der Veröffentlichung: | AMSTERDAM | ||||
Band: | 40 | ||||
Seitenbereich: | S. 406-421 | ||||
Datum: | 2019 | ||||
Institutionen: | Medizin > Lehrstuhl für Pathologie | ||||
Identifikationsnummer: |
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Stichwörter / Keywords: | ACTIVATED PROTEIN-KINASE; TUMOR-SUPPRESSOR LKB1; GLYCINE N-METHYLTRANSFERASE; HYPOXIA-INDUCIBLE FACTOR; HEPATOCELLULAR-CARCINOMA; MOLECULAR-DYNAMICS; SUMO CONJUGATION; C-ZETA; AMPK; PHOSPHORYLATION; LKB1; SUMO; HCC; SIRT1; STRAD alpha | ||||
Dewey-Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin | ||||
Status: | Veröffentlicht | ||||
Begutachtet: | Ja, diese Version wurde begutachtet | ||||
An der Universität Regensburg entstanden: | Ja | ||||
Dokumenten-ID: | 49018 |
Zusammenfassung
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 ...
Zusammenfassung
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 (STRAD alpha), 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 oncogenic role in liver cancer. (C) 2018 The Authors. Published by Elsevier B.V.
Metadaten zuletzt geändert: 03 Sep 2021 10:04