RSK2 and β-Trcp-mediated ubiquitination of FOXN3 impairs DNA damage and confers radioresistance in lung cancer

Aberrant DNA damage responses can result in genomic instability, thereby affecting the efficacy of radiotherapy. The transcription factor FOXN3 plays critical roles in cellular growth and proliferation, inflammation, and the response to injury; however, its involvement in lung cancer radioresistance remains unclear. Here, we revealed that reduced expression of FOXN3 was correlated with poor prognosis in lung adenocarcinoma patients and that FOXN3 depletion impaired the DNA damage response, thereby conferring radioresistance in lung cancer. Mechanistically, FOXN3 promoted BRCA1 transcription by binding to the BRCA1 promoter region, thereby increasing DNA damage. Furthermore, the protein kinase RSK2 and E3 ubiquitin ligase β-Trcp collaboratively interacted with FOXN3, facilitating its ubiquitination-mediated degradation via a conserved DSGYAS motif. Importantly, this cooperative degradation of FOXN3 attenuated DNA damage and promoted radioresistance in lung cancer cells. Our study provides a mechanistic foundation for targeting FOXN3-related pathways as a potential strategy to overcome radioresistance in lung cancer.