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

2019; Springer Science+Business Media; Volume: 138; Issue: 6 Linguagem: Inglês

10.1007/s00401-019-02062-4

1432-0533

Maxime Janin, Vanessa Ortiz-Barahona, Manuel Castro de Moura, Anna Martínez‐Cardús, Pere Llinàs‐Arias, Marta Soler, Daphna Nachmani, Joffrey Pelletier, Ulrike Schümann, María Eréndira Calleja-Cervantes, Sebastián Morán, Sònia Guil, Alberto Bueno-Costa, David Piñeyro, Montserrat Pérez-Salvia, Margalida Rosselló-Tortella, Laia Piqué, Joan Josep Bech‐Serra, Carolina de la Torre, August Vidal, María Martínez‐Iniesta, Juan F. Martín-Tejera, Alberto Villanueva, Alexandra Arias, Isabel Cuartas, Ana M. Aransay, Andrés Morales La Madrid, Ángel M. Carcaboso, Vicente Santa‐María, Jaume Mora, Agustín F. Fernández, Mario F. Fraga, Ibán Aldecoa, Leire Pedrosa, Francesc Graus, Noemí Vidal, Fina Martínez‐Soler, Avelina Tortosa, Cristina Carrato, Carmen 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,

Cancer-related molecular mechanisms research

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.