Lnc1267-hnRNP U interaction promotes radioresistance by inhibiting apoptosis via attenuated RelA/p65 Ser536 phosphorylation

Radiotherapy efficacy is frequently limited by tumor radioresistance, with dysregulated apoptosis playing a pivotal role. While NF-κB is a well-established mediator of cancer radioresistance (primarily through anti-apoptotic mechanisms), the paradoxical pro-apoptotic function of radiation-induced NF-κB activation remains poorly understood. Emerging evidence suggests that certain conserved lncRNAs may function analogously to housekeeping genes during tumor progression; however, their involvement in radiation-triggered apoptotic pathways—particularly NF-κB-dependent pro-apoptotic signaling—during radiotherapy remains unexplored. This study aims to elucidate the functional role and molecular mechanisms through which a novel conserved lncRNA confers cancer radioresistance by regulating the NF-κB-mediated pro-apoptotic pathway. Herein, we identify lnc1267 as a highly conserved lncRNA (80.43% sequence homology between humans and mice) featuring characteristic 3’-poly(A) tail structure without 5’-triphosphate capping. Radiation exposure represses lnc1267 expression, which activates NF-κB pro-apoptotic signaling via RelA/p65 phosphorylation at Ser536. Functionally, lnc1267 confers radioresistance in cancer cells, while its downregulation sensitizes diverse cancer types to irradiation. Mechanistically, radiation-induced p53 activation transcriptionally suppresses lnc1267 through direct promoter binding, thereby releasing hnRNP U to interact with IKKβ and promote RelA/p65-Ser536 phosphorylation-ultimately triggering pro-apoptotic cascades and radiosensitization. Overall, this study demonstrates for the first time the critical role and mechanistic basis of a conserved lncRNA in regulating tumor radioresistance. These findings highlight the essential regulatory function of conserved lncRNAs in modulating radiation-triggered pro-apoptotic signaling and radiosensitivity in cancer cells, thereby expanding our understanding of lncRNAs in cancer radiobiology and providing a novel therapeutic target for radiotherapy-resistant cancers.