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

Maxime Janin, Vanessa Ortiz-Barahona, Manuel Castro de Moura, Anna Martínez-Cardús, Pere Llinàs-Arias, Marta Soler, Daphna Nachmani, Joffrey Pelletier, Ulrike Schumann, Maria E. Calleja-Cervantes, Sebastian Moran, Sonia Guil, Alberto Bueno-Costa, David Piñeyro, Montserrat Perez-Salvia, Margalida Rosselló-Tortella, Laia Piqué, Joan J. Bech-Serra, Carolina De La Torre, August VidalMaría Martínez-Iniesta, Juan F. Martín-Tejera, Alberto Villanueva, Alexandra Arias, Isabel Cuartas, Ana M. Aransay, Andres Morales La Madrid, Angel M. Carcaboso, Vicente Santa-Maria, Jaume Mora, Agustin F. Fernandez, Mario F. Fraga, Iban Aldecoa, Leire Pedrosa, Francesc Graus, Noemi Vidal, Fina Martínez-Soler, Avelina Tortosa, Cristina Carrato, Carme Balañá, Matthew W. Boudreau, Paul J. Hergenrother, Peter Kötter, Karl Dieter Entian, Jürgen Hench, Stephan Frank, Sheila Mansouri, Gelareh Zadeh, Pablo D. Dans, Modesto Orozco, George Thomas, Sandra Blanco, Joan Seoane, Thomas Preiss, Pier Paolo Pandolfi, Manel Esteller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1053-1074
Number of pages22
JournalActa Neuropathologica
Volume138
Issue number6
DOIs
StatePublished - Dec 1 2019

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Keywords

  • Clinical outcome
  • Epitranscriptomics
  • Glioma
  • RNA methylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Janin, M., Ortiz-Barahona, V., de Moura, M. C., Martínez-Cardús, A., Llinàs-Arias, P., Soler, M., Nachmani, D., Pelletier, J., Schumann, U., Calleja-Cervantes, M. E., Moran, S., Guil, S., Bueno-Costa, A., Piñeyro, D., Perez-Salvia, M., Rosselló-Tortella, M., Piqué, L., Bech-Serra, J. J., De La Torre, C., ... Esteller, M. (2019). Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. Acta Neuropathologica, 138(6), 1053-1074. https://doi.org/10.1007/s00401-019-02062-4