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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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Research Article Oncology

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

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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 8

Targeting ADAR1 or GM2A attenuates in vivo tumor growth.

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Targeting ADAR1 or GM2A attenuates in vivo tumor growth.
(A) Survival an...
(A) Survival analysis of NSG mice bearing intracranially implanted patient-derived 3691 GSCs transduced with shCONT or 1 of 2 non-overlapping shADAR1s (left panel). Statistical significance was determined by log-rank (Mantel-Cox) test. GSCs were implanted intracranially into NSG mice, and tumor formation was determined by H&E staining (right panel). Scale bar: 2 mm. n = 5 per group, 2 biological replicates. (B) Survival analysis of NSG mice bearing intracranially implanted patient-derived 3565 GSCs transduced with shCONT or 1 of 2 non-overlapping shADAR1s (left panel). Statistical significance was determined by log-rank (Mantel-Cox) test. GSCs were implanted intracranially into NSG mice, and tumor formation was determined by H&E staining (right panel). Scale bar: 2 mm. n = 5 per group, 2 biological replicates. (C) Survival analysis of NSG mice bearing intracranially implanted patient-derived 3691 GSCs transduced with shCONT or 1 of 2 non-overlapping shGM2As (left panel). Statistical significance was determined by log-rank (Mantel-Cox) test. GSCs were implanted intracranially into NSG mice, and tumor formation was determined by H&E staining (right panel). Scale bar: 2 mm. n = 5 per group. (D) Survival analysis of NSG mice bearing intracranially implanted patient-derived 3565 GSCs transduced with shCONT or 1 of 2 non-overlapping shGM2As (left panel). Statistical significance was determined by log-rank (Mantel-Cox) test. GSCs were implanted intracranially into NSG mice, and tumor formation was determined by H&E staining (right panel). Scale bar: 2 mm. n = 5 per group. **P < 0.01.

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