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.
Highlights
Glioblastomas (GBMs; World Health Organization grade IV gliomas) are the most prevalent and aggressive primary malignant intrinsic brain tumors in adults [1]
Global landscapes of A-to-I RNA editing in GBM stem cells (GSCs)
To elucidate A-to-I RNA editing in GSCs, we interrogated the RNA editomes of 31 patient-derived GSCs and 5 neural stem cells (NSCs) by RNA-Seq [39], using a previously described computational pipeline
Summary
Glioblastomas (GBMs; World Health Organization grade IV gliomas) are the most prevalent and aggressive primary malignant intrinsic brain tumors in adults [1]. GBMs display remarkable cellular heterogeneity, containing stem-like GBM stem cells (GSCs; known as brain tumor–initiating cells) that contribute to therapeutic resistance and rapid recurrence [5–8]. In contrast to non-stem or differentiated GBM cells (DGCs), GSCs express stem cell markers, generate spheres in serum-free conditions, and rapidly form tumors in vivo [9, 10]. Somatic mutations contribute to initiation and progression of GBM, but precision medicine has so far met with limited success in its treatment [11, 12]. Epigenetic alterations may promote gliomagenesis, offering therapeutic targets [13–15]. One recent advance in tumor biology is the attribution of altered A-to-I RNA editing to diverse tumorigenic pathways [16, 17]
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