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 5

The GM2 ganglioside catabolic pathway maintains GSCs.

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The GM2 ganglioside catabolic pathway maintains GSCs. (A) Left: Gene exp...
(A) Left: Gene expression levels of HEXA and HEXB in normal brain and gliomas in TCGA. Statistical significance was determined by Wilcoxon’s signed-rank test. ***P < 0.01. Right: Kaplan-Meier survival curves of glioma patients with high or low HEXA or HEXB expression in TCGA. P value was determined by log-rank test. (B) Pairwise correlation analysis between GM2A, HEXA, and HEXB gene expression data from TCGA GBM data sets. Correlation coefficient (R) values are shown. (C) mRNA expression of HEXA and HEXB in GSCs (3565 and 3691) transduced with shCONT or shGM2A. Quantitative data from 3 independent experiments are shown as mean ± SD (error bars). n = 3. Statistical significance was determined by ANOVA. *P < 0.05, ****P < 0.0001. (D) HEXA (top) and HEXB (bottom) mRNA expression in GSCs (1517, 3565, and 3691) transduced with shCONT, shHEXA, or shHEXB. 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. (E) Proliferation of GSCs (1517, 3565, and 3691) transduced with shCONT or shHEXA determined by CellTiter-Glo. n = 5. Quantitative data from 5 technical experiments are shown as mean ± SD (error bars). Statistical significance was determined by 2-way ANOVA with Dunnett’s multiple-comparison test. ****P < 0.0001. (F) Proliferation of GSCs (1517, 3565, and 3691) transduced with shCONT or shHEXB determined by CellTiter-Glo. n = 5. Quantitative data from 5 technical experiments are shown as mean ± SD (error bars). Statistical significance was determined by 2-way ANOVA with Dunnett’s multiple-comparison test. ****P < 0.0001. (G) ELDA for in vitro sphere formation of GSCs (1517, 3565, and 3691) transduced with shCONT or shHEXA. n = 24. Pairwise tests for differences in stem cell frequencies. ***P < 0.001. (H) Analyses identical to those in G were performed for HEXB.