Zubiete-Franco, Imanol and Garcia-Rodriguez, Juan L. and Lopitz-Otsoa, Fernando and Serrano-Macia, Marina and Simon, Jorge and Fernandez-Tussy, Pablo and Barbier-Torres, Lucia and Fernandez-Ramos, David and Gutierrez-de-Juan, Virginia and Lopez de Davalillo, Sergio and Carlevaris, Onintza and Beguiristain Gomez, Adolfo and Villa, Erica and Calvisi, Diego and Martin, Cesar and Berra, Edurne and Aspichueta, Patricia and Beraza, Naiara and Varela-Rey, Marta and Avila, Matias and Rodriguez, Manuel S. and Mato, Jose M. and Diaz-Moreno, Irene and Diaz-Quintana, Antonio and Delgado, Teresa C. and Martinez-Chantar, Maria L. (2019) SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer. EBIOMEDICINE, 40. pp. 406-421. ISSN 2352-3964,
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled 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 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 08:19 |
| Last Modified: | 22 Apr 2020 08:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27601 |
Actions (login required)
 |
View Item |
