SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma
- 1University of Alabama at Birmingham
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 NF{kappa}B signaling, whereas radiation-resistant GBM cells exhibited enhanced PKR/NF{kappa}B 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.
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BibTeX
@misc{harvey2026sonmediated,
title = {{SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma}},
author = {C. A. Harvey and S. K. Dunlap and M. Mohamed and E. Kudaravalli and A. Elkholy and L. Gehrs and S. Zakakhosravi and B. Park and K. W. Min and J. M. Murphy and O. Iwaloye and S. Osuka and S.-T. S. Lim and C. D. Willey and E. K. Flemington and E.-Y. E. Ahn},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.755153},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.755153v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - SON-mediated circular RNA suppression promotes PKR signaling and radiation resistance in glioblastoma
AU - C. A. Harvey
AU - S. K. Dunlap
AU - M. Mohamed
AU - E. Kudaravalli
AU - A. Elkholy
AU - L. Gehrs
AU - S. Zakakhosravi
AU - B. Park
AU - K. W. Min
AU - J. M. Murphy
AU - O. Iwaloye
AU - S. Osuka
AU - S.-T. S. Lim
AU - C. D. Willey
AU - E. K. Flemington
AU - E.-Y. E. Ahn
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.755153
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.755153v1
AB - 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 NF{kappa}B signaling, whereas radiation-resistant GBM cells exhibited enhanced PKR/NF{kappa}B 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.
ER -