SMC1A drives radioresistance in lung squamous cell carcinoma through the ILF2/RNF2 axis

Although our previous study has highlighted the implication of RING finger protein 2 (RNF2) in radiotherapy (RT) of lung squamous cell carcinoma (LUSC), many questions remain regarding the mechanism. In the study here, we explored the functional role of the axis structural maintenance of chromosomes protein 1 A (SMC1A)/interleukin enhancer-binding factor 2 (ILF2)/RNF2 in radioresistance in LUSC. SMC1A, ILF2, and RNF2 were upregulated in LUSC patients with recurrence after RT and radioresistant LUSC cells. SMC1A activated ILF2 transcription by occupying the ILF2 promoter. ILF2 bound to RNF2 mRNA and induced its expression. Inhibition of ILF2 and SMC1A inhibited DNA damage repair, contributing to the sensitivity of LUSC cells to irradiation. The downregulation of ILF2 and SMC1A curtailed the malignant phenotype of LUSC cells. Restoration of RNF2 and ILF2 reversed the LUSC radiosensitivity and tumor growth inhibition mediated by ILF2 knockdown and SMC1A knockdown. Furthermore, virtual screening suggested that multiple FDA-approved drugs may exhibit structural compatibility with the predicted SMC1A binding pocket. Our work reveals that the SMC1A/ILF2/RNF2 axis shapes RT and malignant progression in LUSC by enhancing DNA damage repair. Inhibiting this axis increases RT-induced DNA damage and enhances treatment response, providing a potential target for radiosensitization in LUSC.