2. Academic Validation
  3. SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer

  • Cell Rep. 2024 Mar 26;43(3):113924. doi: 10.1016/j.celrep.2024.113924.
Sofia Lachiondo-Ortega 1,  Claudia M Rejano-Gordillo 2,  Jorge Simon 3,  Fernando Lopitz-Otsoa 1,  Teresa C Delgado 1,  Krystyna Mazan-Mamczarz 4,  Naroa Goikoetxea-Usandizaga 1,  L Estefanía Zapata-Pavas 1,  Ana García-Del Río 5,  Pietro Guerra 6,  Patricia Peña-Sanfélix 1,  Natalia Hermán-Sánchez 7,  Ruba Al-Abdulla 8,  Carmen Fernandez-Rodríguez 1,  Mikel Azkargorta 9,  Alejandro Velázquez-Cruz 10,  Joris Guyon 11,  César Martín 12,  Juan Diego Zalamea 13,  Leire Egia-Mendikute 5,  Arantza Sanz-Parra 1,  Marina Serrano-Maciá 1,  Irene González-Recio 1,  Monika Gonzalez-Lopez 14,  Luis Alfonso Martínez-Cruz 1,  Patrizia Pontisso 6,  Ana M Aransay 14,  Rosa Barrio 15,  James D Sutherland 15,  Nicola G A Abrescia 16,  Félix Elortza 9,  Amaia Lujambio 17,  Jesus M Banales 18,  Raúl M Luque 7,  Manuel D Gahete 7,  Asís Palazón 19,  Matias A Avila 20,  Jose J G Marin 21,  Supriyo De 4,  Thomas Daubon 22,  Antonio Díaz-Quintana 10,  Irene Díaz-Moreno 10,  Myriam Gorospe 4,  Manuel S Rodríguez 23,  María Luz Martínez-Chantar 24
Affiliations

Affiliations

  • 1 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 2 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Department of Biochemistry and Molecular Biology, Faculty of Sciences, University of Extremadura, University Institute of Biosanitary Research of Extremadura (INUBE), 06071 Badajoz, Spain; Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
  • 3 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain.
  • 4 Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA.
  • 5 Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 6 Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35128 Padua, Italy.
  • 7 Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Department of Cell Biology, Physiology and Immunology of University of Córdoba, Reina Sofia University Hospital, CIBER Pathophysiology of Obesity and Nutrition (CIBERobn), 14004 Córdoba, Spain.
  • 8 Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, Elche, Spain; Institute of Medical Biochemistry and Molecular Biology, University Medicine of Greifswald, 17475 Greifswald, Germany.
  • 9 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Proteomics Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Carlos III Networked Proteomics Platform (ProteoRed-ISCIII), 48160 Derio, Bizkaia, Spain.
  • 10 Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla, Consejo Superior de Investigaciones Científicas (CSIC), Sevilla, Spain.
  • 11 University of Bordeaux, INSERM, BPH, U1219, 33000 Bordeaux, France; CHU de Bordeaux, Service de Pharmacologie Médicale, 33000 Bordeaux, France.
  • 12 Biofisika Institute, Consejo Superior de Investigaciones Científicas (CSIC), Departamento Bioquímica y Biología Molecular, Facultad de Ciencia y Tecnología, Universidad del País Vasco (UPV/EHU), Leioa, Spain.
  • 13 Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 14 Genome Analysis Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 15 Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 16 Structure and Cell Biology of Viruses Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
  • 17 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 18 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
  • 19 Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
  • 20 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Hepatology Program, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain; Instituto de Investigaciones Sanitarias de Navarra (IdiSNA), Pamplona, Spain.
  • 21 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), Instituto de Investigación Biomédica de Salamanca (IBSAL), University of Salamanca, Salamanca, Spain.
  • 22 University of Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France.
  • 23 Laboratoire de Chimie de Coordination (LCC), UPR 8241, CNRS; IPBS-University of Toulouse III-Paul Sabatier, Toulouse, France.
  • 24 Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Health Institute, Madrid, Spain. Electronic address: mlmartinez@cicbiogune.es.
PMID: 38507413 DOI: 10.1016/j.celrep.2024.113924
Abstract

The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver Cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major Cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver Cancer.

Keywords

CP: Cancer; CP: Molecular biology; ELAVL1; HCC; PTMs; SUMO; senescence.

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