ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance
Li Jiang, … , Xiang-Dong Fu, Jeremy N. Rich
Li Jiang, … , Xiang-Dong Fu, Jeremy N. Rich
Published February 8, 2022
Citation Information: J Clin Invest. 2022;132(6):e143397. https://doi.org/10.1172/JCI143397.
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ADAR1-mediated RNA editing links ganglioside catabolism to glioblastoma stem cell maintenance

Abstract

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.

Authors

Li Jiang, Yajing Hao, Changwei Shao, Qiulian Wu, Briana C. Prager, Ryan C. Gimple, Gabriele Sulli, Leo J.Y. Kim, Guoxin Zhang, Zhixin Qiu, Zhe Zhu, Xiang-Dong Fu, Jeremy N. Rich

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Figure 7

Pharmacologic targeting of GSC self-renewal through the ADAR1/GM2 axis.

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Pharmacologic targeting of GSC self-renewal through the ADAR1/GM2 axis. ...
See also Supplemental Figure 5. (A) Gene set enrichment analysis based on KEGG pathway annotation of JAK/STAT signaling pathway genes in GBM informed by TCGA data. (B) ADAR1 and GM2A mRNA expression in 3565 GSCs treated with vehicle control (DMSO) or different concentrations of a TYK2 inhibitor. n = 4. Quantitative data from 4 independent experiments are shown as mean ± SD (error bars). Statistical significance was determined by ANOVA. **P < 0.01. (C) ADAR1 and GM2A mRNA expression in 3691 GSCs treated with vehicle control (DMSO) or several concentrations of a TYK2 inhibitor. n = 4. Quantitative data from 4 independent experiments are shown as mean ± SD (error bars). Statistical significance was determined by ANOVA. **P < 0.01, ***P < 0.001. (D) Western blotting for ADAR1, SOX2, and GM2A in GSCs (1517, 3565, and 3691) treated with vehicle control (DMSO) or TYK2 inhibitor. (E) Comparative concentration response curves for GSCs (1517, 3565, and 3691), matched DGCs (1517, 3565, and 3691), and nonmalignant cells derived from epilepsy surgical specimens (NM176 and NM263) treated with increasing concentrations of a TYK2 inhibitor for 2 days. (F) ELDA for in vitro sphere formation of GSCs (1517, 3565, and 3691) treated with vehicle control (DMSO) or a TYK2 inhibitor. n = 24. Pairwise tests for differences in stem cell frequencies. ***P < 0.001. (G) Cell viability of GSCs (1517, 3565, and 3691; top) and matched DGCs (1517, 3565, and 3691; bottom) with increasing concentrations of desipramine. (H) Cell viability of GSCs (1517, 3565, and 3691; top) and matched DGCs (1517, 3565, and 3691; bottom) with increasing concentrations of chloroquine. (I) Sphere formation of GSCs (1517, 3565, and 3691; top) and matched DGCs (1517, 3565, and 3691; bottom) with DMSO, desipramine, or chloroquine. Scale bars: 50 μm.