, not by mutation, but via epigenomic and 3D-chromatin re-wiring.){kind=link}
A study published in Cancer Gene Therapy demonstrates that the transcription factor AP-1 plays a central role in promoting oncogenic transcription in non-small cell lung cancer (NSCLC), not by mutation, but via epigenomic and 3D-chromatin re-wiring.
Using a comprehensive multi-omic approach including promoter-capture Hi-C, ATAC-seq, ChIP-seq and transcriptomics, the authors compared a well-characterized lung cancer cell line to non-cancerous bronchial epithelial cells, and further validated their findings using patient data from The Cancer Genome Atlas (TCGA).
The cancer cell model faithfully recapitulated key transcriptomic and epigenomic alterations observed in NSCLC patients, supporting its relevance.
Their analysis revealed aberrant activation of AP-1, in a subset of NSCLC samples, with high AP-1 levels correlating with worse survival in lung squamous cell carcinoma.
Mechanistically, they discovered that AP-1 binds to active promoters and enhancers of numerous oncogenes, and mediates stronger promoter–enhancer looping. This physical bridging appears to underlie the elevated expression of oncogenes in tumor cells.
Pharmacological inhibition of AP-1, either directly using the AP-1 inhibitor SR11302 or indirectly via upstream JNK pathway blockade with SP600125, attenuated oncogenic transcription and disrupted promoter-enhancer interactions in cancer cells.
These findings not only clarify how aberrant transcription factor activity can restructure 3D chromatin to foster oncogene expression, but also point to AP-1 or its upstream regulators as a potential therapeutic target in NSCLC.
In sum, this study shifts part of the focus in cancer genomics from purely genetic mutations toward epigenomic and spatial-genome alterations: transcription factors like AP-1 can drive malignant gene expression through rewiring chromatin architecture, without changes in DNA sequence.