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

descriptionPublicationkeyboard_double_arrow_right Article 19 Aug 2019 Spain English Publisher:Springer Science and Business Media LLCJournal:Acta Neuropathologica, volume 138, pages 1,053-1,074 (issn: 0001-6322, eissn: 1432-0533,

Copyright policy )Funded by:NIH | Training Program in Chemi..., EC | EPINORC, NHMRC | Characterising the topolo...

Authors: Maxime Janin; Vanessa Ortiz-Barahona; Manuel Castro de Moura; Anna Martínez-Cardús; Pere Llinàs-Arias; Marta Soler; Daphna Nachmani; +49 Authors

doi: 10.1007/s00401-019-02062-4

pmid: 31428936

pmc: PMC6851045

handle: 10261/210821 , 10651/53070 , 2445/148583 , 11351/5869

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

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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.

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Spain

Related Organizations

University of Illinois at Urbana Champaign
United States
Vall d'Hebron Institute of Oncology (VHIO)
Spain
Australian National University
Australia
University Health Network
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University of Salamanca
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Keywords

Metiltransferases, Outcome assessment (Medical care), Mice, Nude, Muscle Proteins, DISEASES::Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma, :neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma [ENFERMEDADES], CHEMICALS AND DRUGS::Enzymes and Coenzymes::Enzymes::Transferases::One-Carbon Group Transferases::Methyltransferases, Methylation, Epigenesis, Genetic, ENFERMEDADES::neoplasias::neoplasias por tipo histológico::neoplasias de células germinales y embrionarias::tumores neuroectodérmicos::neoplasias neuroepiteliales::glioma, Gliomes, Clinical outcomes, Cell Line, Tumor, RNA, Ribosomal, 28S, Biomarkers, Tumor, Gliomas, Animals, Humans, Epitranscriptomics, Original Paper, Clinical outcome, :enzimas y coenzimas::enzimas::transferasas::transferasas de grupos de un solo carbono::metiltransferasas [COMPUESTOS QUÍMICOS Y DROGAS], Brain Neoplasms, Glioma, Methyltransferases, DNA Methylation, Clinical outcome, Epitranscriptomics, Glioma, RNA methylation, :Neoplasms::Neoplasms by Histologic Type::Neoplasms, Germ Cell and Embryonal::Neuroectodermal Tumors::Neoplasms, Neuroepithelial::Glioma [DISEASES], Protein Biosynthesis, COMPUESTOS QUÍMICOS Y DROGAS::enzimas y coenzimas::enzimas::transferasas::transferasas de grupos de un solo carbono::metiltransferasas, RNA methylation, Avaluació de resultats (Assistència mèdica), RNA, :Enzymes and Coenzymes::Enzymes::Transferases::One-Carbon Group Transferases::Methyltransferases [CHEMICALS AND DRUGS], Metilació, Ribosomes, Neoplasm Transplantation

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