TY - JOUR
T1 - Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
AU - Janin, Maxime
AU - Ortiz-Barahona, Vanessa
AU - de Moura, Manuel Castro
AU - Martínez-Cardús, Anna
AU - Llinàs-Arias, Pere
AU - Soler, Marta
AU - Nachmani, Daphna
AU - Pelletier, Joffrey
AU - Schumann, Ulrike
AU - Calleja-Cervantes, Maria E.
AU - Moran, Sebastian
AU - Guil, Sonia
AU - Bueno-Costa, Alberto
AU - Piñeyro, David
AU - Perez-Salvia, Montserrat
AU - Rosselló-Tortella, Margalida
AU - Piqué, Laia
AU - Bech-Serra, Joan J.
AU - De La Torre, Carolina
AU - Vidal, August
AU - Martínez-Iniesta, María
AU - Martín-Tejera, Juan F.
AU - Villanueva, Alberto
AU - Arias, Alexandra
AU - Cuartas, Isabel
AU - Aransay, Ana M.
AU - La Madrid, Andres Morales
AU - Carcaboso, Angel M.
AU - Santa-Maria, Vicente
AU - Mora, Jaume
AU - Fernandez, Agustin F.
AU - Fraga, Mario F.
AU - Aldecoa, Iban
AU - Pedrosa, Leire
AU - Graus, Francesc
AU - Vidal, Noemi
AU - Martínez-Soler, Fina
AU - Tortosa, Avelina
AU - Carrato, Cristina
AU - Balañá, Carme
AU - Boudreau, Matthew W.
AU - Hergenrother, Paul J.
AU - Kötter, Peter
AU - Entian, Karl Dieter
AU - Hench, Jürgen
AU - Frank, Stephan
AU - Mansouri, Sheila
AU - Zadeh, Gelareh
AU - Dans, Pablo D.
AU - Orozco, Modesto
AU - Thomas, George
AU - Blanco, Sandra
AU - Seoane, Joan
AU - Preiss, Thomas
AU - Pandolfi, Pier Paolo
AU - Esteller, Manel
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
KW - Clinical outcome
KW - Epitranscriptomics
KW - Glioma
KW - RNA methylation
UR - http://www.scopus.com/inward/record.url?scp=85070822137&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02062-4
DO - 10.1007/s00401-019-02062-4
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C2 - 31428936
AN - SCOPUS:85070822137
SN - 0001-6322
VL - 138
SP - 1053
EP - 1074
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -
