AP-1 promotes oncogenic transcription in lung cancer cells by bridging promoter-enhancer interactions

Mechanistic understanding of how transcription factors drive oncogene expression in lung cancer remains limited. Here, we utilized a cancer cell line-guided, multi-omic approach integrating promoter-capture Hi-C (pcHiC), ATAC-seq, ChIP-seq, and transcriptomics to identify epigenomic and 3D genomic alterations associated with oncogenes in non-small cell lung cancer (NSCLC) patients from The Cancer Genome Atlas (TCGA). Our cancer cell line accurately recapitulates key transcriptomic and epigenomic alterations observed in NSCLC patient samples. Comprehensive multi-omic analyses revealed aberrant activation of the bZIP family oncogenic transcription factor AP-1 in lung cancer cells. Clinically, AP-1 activation significantly correlated with patient outcomes in TCGA data, where elevated AP-1 expression levels were associated with increased mortality in lung squamous cell carcinoma patients. UMAP projections further demonstrated that AP-1-driven oncogene expression is specifically enriched in NSCLC patients exhibiting high AP-1 expression levels. Mechanistically, we observed enhanced promoter-enhancer interactions mediated by AP-1 at multiple upregulated oncogenes. Pharmacological inhibition of AP-1, either directly via AP-1 inhibitor SR11302 or indirectly through its upstream JNK pathway inhibition via SP600125, suppressed AP-1-driven oncogenic transcription and reduced promoter-enhancer looping. Our findings highlight the pivotal role of AP-1 in oncogenic transcription in NSCLC, revealing that transcription factors enhance oncogene expression by facilitating promoter-enhancer interactions.