SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma

Glioblastoma (GBM) shows a significant reduction in circular RNAs (circRNAs), but the underlying mechanisms and their implications are not well understood. Researchers have now discovered that the splicing co-factor SON serves as a suppressor of circRNA biogenesis in GBM. When SON activity is diminished, there is a noticeable rise in circRNA levels.

Conversely, higher SON expression in GBM, especially in radiation-resistant models, is linked to decreased circRNA abundance, particularly for circUSP1 and circSUCO. When SON levels are reduced, there is an increase in circRNA abundance and a decrease in the activation of dsRNA-responsive kinase PKR and downstream NF-κB signaling.

Notably, radiation-resistant GBM cells display enhanced PKR/NF-κB activation, which is suppressed by SON depletion. Importantly, the overexpression of circUSP1 and circSUCO, which are typically suppressed by SON, reduces PKR activation and significantly decreases the survival of radiation-resistant GBM cells in clonogenic assays, without affecting the non-resistant cells.

These findings unveil a previously unidentified SON/circRNA/PKR regulatory pathway that connects RNA processing to acquired radiation resistance in GBM. This research also highlights specific PKR-inhibitory circRNAs as potential therapeutic targets to sensitize radiation-resistant GBM to radiotherapy.