TFAP2A enhances radioresistance of non-small cell lung cancer by transcriptionally activating BRCA1

Radioresistance remains a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Transcription factor AP-2α (TFAP2A) has been implicated in tumor progression, but its role in NSCLC radioresistance and translational therapeutic relevance remain unclear. Bioinformatics analyses of TCGA and GEO datasets were used to identify transcription factors associated with NSCLC radioresponse. TFAP2A expression was evaluated in NSCLC tissues by immunohistochemistry. The functional role of TFAP2A was investigated using gain- and loss-of-function experiments in NSCLC cells, xenograft models, and patient-derived NSCLC organoids. Mechanistic studies included RNA sequencing, DNA damage repair assays, dual-luciferase reporter assays, chromatin immunoprecipitation, BRCA1 rescue experiments, and extended DNA damage response pathway validation. Structure-based virtual screening, surface plasmon resonance analysis, clonogenic survival assays, and xenograft experiments were performed to assess TFAP2A-targeted radiosensitization. TFAP2A was overexpressed in NSCLC tissues and was associated with poor prognosis and reduced radiotherapy response. TFAP2A knockdown enhanced radiosensitivity by reducing post-irradiation proliferative recovery, increasing apoptosis, inducing G2/M accumulation, and impairing DNA damage repair, whereas TFAP2A overexpression promoted radioresistance. TFAP2A directly bound to the BRCA1 promoter and transcriptionally activated BRCA1. BRCA1 restoration partially rescued the radiosensitizing effects and G2/M accumulation induced by TFAP2A knockdown. Extended validation of representative DNA damage response pathways and additional RNA-seq-derived repair candidates further supported BRCA1 as a principal downstream effector in this model. Patient-derived NSCLC organoids confirmed that TFAP2A knockdown enhanced radiosensitivity in a clinically derived ex vivo model. Pharmacological validation identified Dephospho-CoA as a candidate TFAP2A-binding compound that enhanced radiotherapy response in clonogenic assays and xenograft models. TFAP2A promotes NSCLC radioresistance by transcriptionally activating BRCA1 and enhancing DNA damage repair. The TFAP2A/BRCA1 axis may serve as a predictive biomarker and therapeutic target for overcoming radioresistance, and TFAP2A-targeted radiosensitization warrants further preclinical development.