Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
Por:
Janin M, Ortiz-Barahona V, de Moura MC, Martínez-Cardús A, Llinàs-Arias P, Soler-Vila M, Nachmani D, Pelletier J, Schumann U, Calleja-Cervantes ME, Moran S, Guil S, Bueno-Costa A, Piñeyro D, Perez-Salvia M, Rosselló-Tortella M, Piqué L, Bech-Serra JJ, De La Torre C, Vidal A, Martínez-Iniesta M, Martín-Tejera JF, Villanueva A, Arias A, Cuartas I, Aransay AM, Morales-La Madrid A, Carcaboso AM, Santa-María López V, Mora J, Fernandez AF, Fraga MF, Aldecoa I, Pedrosa L, Graus F, Vidal N, Martínez-Soler F, Tortosa A, Carrato C, Balañá C, Boudreau MW, Hergenrother PJ, Kötter P, Entian KD, Hench J, Frank S, Mansouri S, Zadeh G, Dans PD, Orozco M, Thomas G, Blanco S, Seoane J, Preiss T, Pandolfi PP and Esteller M
Publicada:
1 dic 2019
Ahead of Print:
19 ago 2019
Resumen:
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.
Filiaciones:
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-Vila 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
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, 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
Morales-La Madrid A:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain
Pediatric Neuro-Oncology Unit, 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-María López V:
Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain
Pediatric Neuro-Oncology Unit, 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
Department of Biochemistry and Biomedicine, University of Barcelona, 08028, Barcelona, 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
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH, 45267-0508, USA
Blanco S:
CIC bioGUNE, 801A Bizkaia Technology Park, 48160, Derio, Spain
Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC), University of Salamanca, 37007, Salamanca, Spain
Seoane J:
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain
Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, 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
Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), NSW, 2010, 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.
Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
Department of Biochemistry and Biomedicine, University of Barcelona, 08028, Barcelona, Spain.
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Barcelona, Catalonia, Spain.
Green Submitted, hybrid
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