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

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-associ...

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Authors: Janin, Maxime|||0000-0003-1013-4128; Ortiz-Barahona, V.; de Moura, M. C.; Martínez Cardús, Anna|||0000-0002-3937-8794; Llinàs-Arias, Pere|||0000-0002-3666-0532; Soler, Marta|||0000-0002-6656-957X; Nachmani, D.; Pelletier, Joffrey|||0000-0001-9174-044X; Schumann, U.; Calleja-Cervantes, María Eréndira|||0000-0003-0688-0793; Moran, S.|||0000-0003-4192-8983; Guil, Sonia|||0000-0002-2257-3331; Bueno-Costa, Alberto|||0000-0001-8700-2540; Piñeyro, David|||0000-0001-5633-3339; Perez-Salvia, Montserrat; Rosselló-Tortella, M.; Piqué, Laia; Bech-Serra, Joan-Josep|||0000-0003-3486-781X; De La Torre Gómez, Gisela Carolina|||0000-0001-9363-291X; Vidal, August|||0000-0001-5727-2099; Martínez-Iniesta, M.; Martín-Tejera, J. F.; Villanueva, Alejandro|||0000-0001-5164-0006; Arias, Alexandra; Cuartas, Isabel; Aransay, Ana M.|||0000-0002-8271-612X; La Madrid, A. M.; Carcaboso, Angel M.|||0000-0002-8485-426X; Santa-Maria, V.; Mora, J.; Fernández, Agustín F.|||0000-0002-3792-4085; Fraga, M. F.; Aldecoa, Iban|||0000-0001-5774-7453; Pedrosa, Leire|||0000-0002-1852-4975; Graus Ribas, Francesc|||0000-0002-8924-8322; Vidal, Noemí|||0000-0002-2852-6667; Martinez, Fina|||0000-0002-0940-1025; Tortosa, Avelina|||0000-0002-9080-2976; Carrato, Cristina|||0000-0002-1953-8287; Balañá, Carmen|||0000-0003-0771-0390; Boudreau, M. W.; Hergenrother, P. J.; Kötter, P.; Entian, K. D.; Hench, Jürgen; Frank, Stephan|||0000-0001-6165-0187; Mansouri, S.; Zadeh, G.; Dans, P. D.; Orozco López, Modesto|||0000-0002-8608-3278; Thomas, Gareth J.; Blanco, Sandra; Seoane Suárez, Joan|||0000-0002-6541-5974; Preiss, T.; Pandolfi, P. P.; Esteller, M.|||0000-0003-4490-6093
Format: Article
Publication date:2019
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:223379
Online Access:https://ddd.uab.cat/record/223379
https://dx.doi.org/urn:doi:10.1007/s00401-019-02062-4
Access Level:Open access
Keyword:Glioma
Epitranscriptomics
RNA methylation
Clinical outcome
Summary: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.

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