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 language | American English |
|---|---|
| Pages (from-to) | 1053-1074 |
| Number of pages | 22 |
| Journal | Acta Neuropathologica |
| Volume | 138 |
| Issue number | 6 |
| DOIs | |
| State | Published - 1 Dec 2019 |
| Externally published | Yes |
Bibliographical note
Funding Information:We would like to thank the IDIBAPS Biobank and the IGTP-HUGTP Biobank (PT13/0010/0009), integrated in the Spanish National Biobank Network at the Instituto de Salud Carlos III, and to the Xarxa de Bancs de Tumors de Catalunya (XBTC), supported by the Pla Director d’Oncologia de Catalunya, for sample and data procurement. We acknowledge technical support from the Australian Cancer Research Foundation Biomolecular Resource Facility at JCSMR, ANU. We thank CERCA Program/Generalitat de Catalunya for their institutional support.
Funding Information:
This work was supported by a European Research Council (ERC) Advanced Grant under the European Community’s Seventh Framework Program (FP7/2007-2013)/ERC Grant Agreement No. 268626—EPINORC project (to M. Esteller), the Ministerio de Economía y Competitividad (MINECO) under Grant No. SAF2014-55000-R (to M. Esteller) and the Instituto de Salud Carlos III (ISCIII), under the FIS PI16/01278 Project (to J. Seoane), the Integrated Project of Excellence no. PIE13/00022 (ONCOPROFILE) (to M. Esteller), CIBER 2016 CB16/12/00312 (CIBERONC) (to M. Esteller), co-financed by the European Development Regional Fund, ‘A way to achieve Europe’ ERDF, the AGAUR—Catalan Government (Project No. 2009SGR1315 and 2014SGR633) (to M. Esteller), the Cellex Foundation (to M. Esteller), Obra Social “La Caixa” (to M. Esteller), the CERCA Program and the Health and Science Departments of the Catalan Government (Generalitat de Catalunya) (to M. Esteller) and a grant from the National Health and Medical Research Council of Australia (APP1061551, to TP). M.W. Boudreau is a member of the NIH Chemistry-Biology Interface Training Program (T32-GM070421). Acknowledgements
Funding Information:
We would like to thank the IDIBAPS Biobank and the IGTP-HUGTP Biobank (PT13/0010/0009), integrated in the Spanish National Biobank Network at the Instituto de Salud Carlos III, and to the Xarxa de Bancs de Tumors de Catalunya (XBTC), supported by the Pla Director d’Oncologia de Catalunya, for sample and data procurement. We acknowledge technical support from the Australian Cancer Research Foundation Biomolecular Resource Facility at JCSMR, ANU. We thank CERCA Program/Generalitat de Catalunya for their institutional support.
Publisher Copyright:
© 2019, The Author(s).
Keywords
- Clinical outcome
- Epitranscriptomics
- Glioma
- RNA methylation
