Cell Reports (Mar 2024)
SUMOylation controls Hu antigen R posttranscriptional activity in liver cancer
- Sofia Lachiondo-Ortega,
- Claudia M. Rejano-Gordillo,
- Jorge Simon,
- Fernando Lopitz-Otsoa,
- Teresa C. Delgado,
- Krystyna Mazan-Mamczarz,
- Naroa Goikoetxea-Usandizaga,
- L. Estefanía Zapata-Pavas,
- Ana García-del Río,
- Pietro Guerra,
- Patricia Peña-Sanfélix,
- Natalia Hermán-Sánchez,
- Ruba Al-Abdulla,
- Carmen Fernandez-Rodríguez,
- Mikel Azkargorta,
- Alejandro Velázquez-Cruz,
- Joris Guyon,
- César Martín,
- Juan Diego Zalamea,
- Leire Egia-Mendikute,
- Arantza Sanz-Parra,
- Marina Serrano-Maciá,
- Irene González-Recio,
- Monika Gonzalez-Lopez,
- Luis Alfonso Martínez-Cruz,
- Patrizia Pontisso,
- Ana M. Aransay,
- Rosa Barrio,
- James D. Sutherland,
- Nicola G.A. Abrescia,
- Félix Elortza,
- Amaia Lujambio,
- Jesus M. Banales,
- Raúl M. Luque,
- Manuel D. Gahete,
- Asís Palazón,
- Matias A. Avila,
- Jose J. G. Marin,
- Supriyo De,
- Thomas Daubon,
- Antonio Díaz-Quintana,
- Irene Díaz-Moreno,
- Myriam Gorospe,
- Manuel S. Rodríguez,
- María Luz Martínez-Chantar
Affiliations
- Sofia Lachiondo-Ortega
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Claudia M. Rejano-Gordillo
- 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
- Jorge Simon
- 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
- Fernando Lopitz-Otsoa
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Teresa C. Delgado
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Krystyna Mazan-Mamczarz
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
- Naroa Goikoetxea-Usandizaga
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- L. Estefanía Zapata-Pavas
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Ana García-del Río
- Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Pietro Guerra
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35128 Padua, Italy
- Patricia Peña-Sanfélix
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Natalia Hermán-Sánchez
- 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
- Ruba Al-Abdulla
- 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
- Carmen Fernandez-Rodríguez
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Mikel Azkargorta
- 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
- Alejandro Velázquez-Cruz
- 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
- Joris Guyon
- University of Bordeaux, INSERM, BPH, U1219, 33000 Bordeaux, France; CHU de Bordeaux, Service de Pharmacologie Médicale, 33000 Bordeaux, France
- César Martín
- 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
- Juan Diego Zalamea
- 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
- Leire Egia-Mendikute
- Cancer Immunology and Immunotherapy Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Arantza Sanz-Parra
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Marina Serrano-Maciá
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Irene González-Recio
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Monika Gonzalez-Lopez
- Genome Analysis Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Luis Alfonso Martínez-Cruz
- Liver Disease Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Patrizia Pontisso
- Unit of Internal Medicine and Hepatology (UIMH), Department of Medicine (DIMED), University of Padova, 35128 Padua, Italy
- Ana M. Aransay
- Genome Analysis Platform, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Rosa Barrio
- Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- James D. Sutherland
- Ubiquitin-likes and Development Lab, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
- Nicola G.A. Abrescia
- 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
- Félix Elortza
- 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
- Amaia Lujambio
- 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
- Jesus M. Banales
- 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
- Raúl M. Luque
- 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
- Manuel D. Gahete
- 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
- Asís Palazón
- 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
- Matias A. Avila
- 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
- Jose J. G. Marin
- 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
- Supriyo De
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
- Thomas Daubon
- University of Bordeaux, CNRS, IBGC, UMR 5095, Bordeaux, France
- Antonio Díaz-Quintana
- 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
- Irene Díaz-Moreno
- 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
- Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging (NIA), Intramural Research Program (IRP), National Institutes of Health (NIH), Baltimore, MD, USA
- Manuel S. Rodríguez
- Laboratoire de Chimie de Coordination (LCC), UPR 8241, CNRS; IPBS-University of Toulouse III-Paul Sabatier, Toulouse, France
- María Luz Martínez-Chantar
- 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; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 3
p. 113924
Abstract
Summary: 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.
