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

Acta Neuropathol. 2019 Dec;138(6):1053-1074. doi: 10.1007/s00401-019-02062-4. Epub 2019 Aug 19.


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.

Keywords: Clinical outcome; Epitranscriptomics; Glioma; RNA methylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenesis, Genetic*
  • Glioma / metabolism*
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice, Nude
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Neoplasm Transplantation
  • Protein Biosynthesis / physiology*
  • RNA, Ribosomal, 28S
  • Ribosomes / metabolism*


  • Biomarkers, Tumor
  • Muscle Proteins
  • RNA, Ribosomal, 28S
  • Methyltransferases
  • NSUN5 protein, human