ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance

J Clin Invest. 2022 Mar 15;132(6):e143397. doi: 10.1172/JCI143397.


Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor, containing GBM stem cells (GSCs) that contribute to therapeutic resistance and relapse. Exposing potential GSC vulnerabilities may provide therapeutic strategies against GBM. Here, we interrogated the role of adenosine-to-inosine (A-to-I) RNA editing mediated by adenosine deaminase acting on RNA 1 (ADAR1) in GSCs and found that both ADAR1 and global RNA editomes were elevated in GSCs compared with normal neural stem cells. ADAR1 inactivation or blocking of the upstream JAK/STAT pathway through TYK2 inhibition impaired GSC self-renewal and stemness. Downstream of ADAR1, RNA editing of the 3'-UTR of GM2A, a key ganglioside catabolism activator, proved to be critical, as interference with ganglioside catabolism and disruption of ADAR1 showed a similar functional impact on GSCs. These findings reveal that RNA editing links ganglioside catabolism to GSC self-renewal and stemness, exposing a potential vulnerability of GBM for therapeutic intervention.

Keywords: Brain cancer; Human stem cells; Oncology; Stem cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Deaminase / genetics
  • Gangliosides / metabolism
  • Glioblastoma* / metabolism
  • Humans
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Neoplasm Recurrence, Local / metabolism
  • Neoplastic Stem Cells / pathology
  • Neural Stem Cells* / metabolism
  • RNA
  • RNA Editing
  • RNA-Binding Proteins / metabolism*
  • STAT Transcription Factors
  • Signal Transduction / genetics


  • Gangliosides
  • RNA-Binding Proteins
  • STAT Transcription Factors
  • RNA
  • Janus Kinases
  • Adenosine Deaminase