SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma
Year: 2026
Type: preprint
Abstract: Glioblastoma (GBM) exhibits extensive loss of circular RNAs (circRNAs), yet the mechanisms driving this depletion and its functional consequences remain unclear. Here, we identify the splicing co-factor SON as a previously unrecognized suppressor of circRNA biogenesis in GBM. CircRNA sequencing revealed widespread increases in circRNA abundance following SON knockdown. Conversely, elevated SON expression in GBM, with further increases in radiation-resistant models, was associated with widespread circRNA loss, including reduced expression of circUSP1 and circSUCO. SON knockdown increased circRNA abundance and attenuated activation of the dsRNA-responsive kinase PKR and downstream NFκB signaling, whereas radiation-resistant GBM cells exhibited enhanced PKR/NFκB activation that was attenuated by SON depletion. Importantly, overexpression of the SON-suppressed circRNAs circUSP1 and circSUCO reduced PKR activation and selectively decreased clonogenic survival following irradiation in radiation-resistant GBM cells, with little effect on parental cells. Together, these findings identify a previously unrecognized SON/circRNA/PKR regulatory pathway linking RNA processing to acquired radiation resistance in GBM and highlight specific PKR-inhibitory circRNAs as potential therapeutic tools for resensitizing radiation-resistant GBM to radiotherapy.
Language: English
Topic: Circular RNAs in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: FAK regulation of cholesterol influx and efflux in foam cells, SON-mediated RNA splicing in glioblastoma, Cancer Prevention and Control Training Program, Targeting Radiation-Induced Glioblastoma Invasion, Genetic and molecular basis of hematopoietic abnormalities in ZTTK syndrome, Nuclear FAK-mediated VSMC differentiation via epigenetic reprograming invascular diseases, UAB Predoctoral Training Grant in Translational and Molecular Sciences
OpenAlex ID: W7214700929