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

  • Acta Neuropathol. 2019 Dec;138(6):1053-1074. doi: 10.1007/s00401-019-02062-4.
Maxime Janin  1 ,  Vanessa Ortiz-Barahona  1 ,  Manuel Castro de Moura  1 ,  Anna Martínez-Cardús  1 ,  Pere Llinàs-Arias  1 ,  Marta Soler  1 ,  Daphna Nachmani  2 ,  Joffrey Pelletier  3 ,  Ulrike Schumann  4 ,  Maria E Calleja-Cervantes  1 ,  Sebastian Moran  1 ,  Sonia Guil  1 ,  Alberto Bueno-Costa  1 ,  David Piñeyro  1 ,  Montserrat Perez-Salvia  1 ,  Margalida Rosselló-Tortella  1 ,  Laia Piqué  1 ,  Joan J Bech-Serra  5 ,  Carolina De La Torre  5 ,  August Vidal  6  7 ,  María Martínez-Iniesta  8 ,  Juan F Martín-Tejera  8 ,  Alberto Villanueva  8 ,  Alexandra Arias  9 ,  Isabel Cuartas  9 ,  Ana M Aransay  10 ,  Andres Morales La Madrid  11  12 ,  Angel M Carcaboso  13 ,  Vicente Santa-Maria  11  12 ,  Jaume Mora  11 ,  Agustin F Fernandez  14 ,  Mario F Fraga  15 ,  Iban Aldecoa  16 ,  Leire Pedrosa  17 ,  Francesc Graus  18 ,  Noemi Vidal  6 ,  Fina Martínez-Soler  19 ,  Avelina Tortosa  19 ,  Cristina Carrato  20 ,  Carme Balañá  21 ,  Matthew W Boudreau  22 ,  Paul J Hergenrother  22 ,  Peter Kötter  23 ,  Karl-Dieter Entian  23 ,  Jürgen Hench  24 ,  Stephan Frank  24 ,  Sheila Mansouri  25 ,  Gelareh Zadeh  25 ,  Pablo D Dans  26 ,  Modesto Orozco  26  27 ,  George Thomas  3  28  29 ,  Sandra Blanco  30  31 ,  Joan Seoane  7  9  32 ,  Thomas Preiss  4  33 ,  Pier Paolo Pandolfi  2 ,  Manel Esteller  34  35  36  37  38
Affiliations
  • 1. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • 2. Department of Medicine and Pathology, Cancer Research Institute, Beth Israel Deaconess Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
  • 3. Molecular Mechanisms and Experimental Therapy in Oncology Program, Metabolism and Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • 4. 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.
  • 5. Proteomics Unit, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
  • 6. Department of Pathology, Hospital Universitari de Bellvitge, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • 7. Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain.
  • 8. 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.
  • 9. Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
  • 10. Centro de Investigación Bimédica en Red de Enfermedades hepáticas y Digestivas (CIBERehd), CIC bioGUNE, 801A Bizkaia Technology Park, 48160, Derio, Spain.
  • 11. Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • 12. Pediatric Neuro-Oncology Unit, Department of Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Catalonia, Spain.
  • 13. Preclinical Therapeutics and Drug Delivery Research Program, Fundacio Sant Joan de Deu, Barcelona, Catalonia, Spain.
  • 14. Institute of Oncology of Asturias (IUOPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA-FINBA), 33011, Oviedo, Spain.
  • 15. Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo-Principado de Asturias, Oviedo, Spain.
  • 16. Pathology-Brain Bank, Hospital Clínic de Barcelona-CDB-August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Catalonia, Spain.
  • 17. Glioma and Neural Stem Cell Group and Translational Genomics and Targeted Therapeutics in Solid Tumors Team, IDIBAPS, Barcelona, Catalonia, Spain.
  • 18. Clinical and Experimental Neuroimmunology, IDIBAPS, Barcelona, Catalonia, Spain.
  • 19. Faculty of Medicine and Health Sciences-Bellvitge, Universitat de Barcelona, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Catalonia, Spain.
  • 20. Department of Pathology, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain.
  • 21. Catalan Institute of Oncology, Hospital Germans Trias i Pujol, 08916, Badalona, Barcelona, Catalonia, Spain.
  • 22. Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
  • 23. Institute for Molecular Biosciences, Goethe University, Frankfurt, Germany.
  • 24. Division of Neuropathology, Institute of Medical Genetics and Pathology, University Hospital Basel, 4031, Basel, Switzerland.
  • 25. Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
  • 26. 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.
  • 27. Department of Biochemistry and Biomedicine, University of Barcelona, 08028, Barcelona, Spain.
  • 28. Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.
  • 29. Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH, 45267-0508, USA.
  • 30. CIC bioGUNE, 801A Bizkaia Technology Park, 48160, Derio, Spain.
  • 31. 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.
  • 32. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
  • 33. Victor Chang Cardiac Research Institute, Darlinghurst (Sydney), NSW, 2010, Australia.
  • 34. Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain. [email protected].
  • 35. Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain. [email protected].
  • 36. Department of Biochemistry and Biomedicine, University of Barcelona, 08028, Barcelona, Spain. [email protected].
  • 37. Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. [email protected].
  • 38. Josep Carreras Leukaemia Research Institute (IJC), Ctra de Can Ruti, Camí de les Escoles s/n, 08916, Badalona, Barcelona, Catalonia, Spain. [email protected].
PMID: 31428936 DOI: 10.1007/s00401-019-02062-4
Abstract

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.

Keywords
Clinical outcome; Epitranscriptomics; Glioma; RNA methylation.