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

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.

Automated summary

This study reveals the role of A-to-I RNA editing mediated by ADAR1 in GBM stem cells and its potential as a therapeutic strategy. The elevated expression of ADAR1 and global RNA editomes in GSCs suggest their involvement in therapeutic resistance and relapse. Inhibition of ADAR1 or the upstream JAK/STAT pathway impairs GSC self-renewal and stemness. Additionally, the study highlights the critical role of RNA editing in ganglioside catabolism and its impact on GSCs.