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Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program.

  • Janin M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Ortiz-Barahona V Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • de Moura MC Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Martínez-Cardús A Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Llinàs-Arias P Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Soler M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Nachmani D Department of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Pelletier J Molecular Mechanisms and Experimental Therapy in Oncology Program, Metabolism and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Schumann U EMBL-Australia Collaborating Group, Department of Genome Sciences, The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, ACT, 2601, Australia.
  • Calleja-Cervantes ME Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Moran S Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Guil S Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Bueno-Costa A Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Piñeyro D Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Perez-Salvia M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Rosselló-Tortella M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Piqué L Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Bech-Serra JJ Proteomics Unit, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • De La Torre C Proteomics Unit, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Vidal A Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Martínez-Iniesta M Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Martín-Tejera JF Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Villanueva A Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Oncobell Program, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Arias A Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
  • Cuartas I Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
  • Aransay AM Centro de Investigación Bimédica en Red de Enfermedades hepáticas y Digestivas (CIBERehd), CIC bioGUNE, 801A Bizkaia Technology Park, 48160, Derio, Spain.
  • La Madrid AM Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • Carcaboso AM Preclinical Therapeutics and Drug Delivery Research Program, Fundacio Sant Joan de Deu, Barcelona, Catalonia, Spain.
  • Santa-Maria V Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • Mora J Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • Fernandez AF Institute of Oncology of Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA-FINBA), 33011, Oviedo, Spain.
  • Fraga MF Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Oviedo, Spain.
  • Aldecoa I Pathology-Brain Bank, Hospital Clínic de Barcelona-CDB-August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Catalonia, Spain.
  • Pedrosa L Glioma and Neural Stem Cell Group and Translational Genomics and Targeted Therapeutics in Solid Tumors Team, IDIBAPS, Barcelona, Catalonia, Spain.
  • Graus F Clinical and Experimental Neuroimmunology, IDIBAPS, Barcelona, Catalonia, Spain.
  • Vidal N Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Martínez-Soler F Faculty of Medicine and Health Sciences-Bellvitge, Universitat de Barcelona, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Tortosa A Faculty of Medicine and Health Sciences-Bellvitge, Universitat de Barcelona, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • Carrato C Department of Pathology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain.
  • Balañá C Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916, Badalona, Barcelona, Catalonia, Spain.
  • Boudreau MW Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • Hergenrother PJ Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • Kötter P Institute for Molecular Biosciences, Goethe University, Frankfurt, Germany.
  • Entian KD Institute for Molecular Biosciences, Goethe University, Frankfurt, Germany.
  • Hench J Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
  • Frank S Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
  • Mansouri S Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
  • Zadeh G Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
  • Dans PD Joint IRB-BSC Program on Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Catalonia, Spain.
  • Orozco M Joint IRB-BSC Program on Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Catalonia, Spain.
  • Thomas G Molecular Mechanisms and Experimental Therapy in Oncology Program, Metabolism and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • Blanco S CIC bioGUNE, 801A Bizkaia Technology Park, 48160, Derio, Spain.
  • Seoane J Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
  • Preiss T EMBL-Australia Collaborating Group, Department of Genome Sciences, The John Curtin School of Medical Research, The Australian National University, Garran Road, Acton, ACT, 2601, Australia.
  • Pandolfi PP Department of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • Esteller M Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. mesteller@carrerasresearch.org.
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  • 2019-08-21
Published in:
  • Acta neuropathologica. - 2019
Clinical outcome
Epitranscriptomics
Glioma
RNA methylation
Animals
Biomarkers, Tumor
Brain Neoplasms
Cell Line, Tumor
DNA Methylation
Epigenesis, Genetic
Glioma
Humans
Methyltransferases
Mice, Nude
Muscle Proteins
Neoplasm Transplantation
Protein Biosynthesis
RNA, Ribosomal, 28S
Ribosomes
English Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/50011
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