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

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 1

Global landscapes of A-to-I RNA editing in GSCs.

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Global landscapes of A-to-I RNA editing in GSCs. See also Supplemental F...
See also Supplemental Figure 1. (A) Distribution of 12 types of RNA editing events in GBM stem cells (GSCs) and neural stem cells (NSCs). Data represent the mean number of inferred RNA editing events detected in GSCs and NSCs. (B) The comparative distribution of A-to-I RNA editing levels in GSCs relative to NSCs. P value was determined by Wilcoxon’s signed-rank test. (C) The distribution of A-to-I RNA editing levels in normal NSCs and different subtypes of GSCs. Statistical significance was determined by Wilcoxon’s signed-rank test and adjusted using the Bonferroni method. ***P < 0.001. (D) Gene set enrichment analysis of GSC stemness gene feature with different A-to-I RNA editing patterns. (E) The distribution of A-to-I RNA editing events in different types of Alu subfamilies. (F) The distribution and percentage of A-to-I RNA editing events in different regions of RNA transcripts in GSCs. (G) The distribution and percentage of A-to-I RNA editing events in different regions on RNA transcripts in NSCs. (H) The distribution of editing percentage of genes ranked by editing level. Eighty-six genes were defined as having GSC-specific editing, and 30 genes were defined as having NSC-specific editing. (I) The 10 genes, among those defined in H as having GSC-specific editing, with the highest levels of editing and dysregulation in cancer biology are depicted. (J) Relative frequency of A-to-I RNA editing events in low-grade and high-grade gliomas in TCGA (17). Statistical significance was determined by Wilcoxon’s signed-rank test. ***P < 0.001.