The lineage master transcription factor, p63 recruits a cancer-specific cofactor, FOXK1 to mediate oncogenic 3D chromatin dynamics in squamous cell carcinoma[ATAC-seq]

Transcriptional dysregulation by a lineage master transcription factor (TF) is a critical mechanism in cancer, involving alteration of three-dimensional (3D) chromatin architecture. However, the underlying mechanisms of altered master TF-dependent chromatin interactions in cancer cells remain unclear. Here, we employ multi-omic approaches to examine chromatin interactions dependent on p63, a master TF in epidermis, in squamous cell carcinomas (SCCs) compared to normal keratinocytes (KCs), integrating chromatin looping and accessibility, transcriptome, p63 binding and proteomics. p63 facilitates higher connectivity between the promoters of prognostic genes in SCCs, and distal enhancers. Many SCC-specific p63-dependent genes are connected to SCC-specific p63-dependent epigenetic signature via a cis-regulatory element (CRE) without the signature, referred to as ‘Secondary’ regulation mode. Notably, we identify FOXK1 as a cancer-specific cofactor, cooperating with p63 to shape the oncogenic chromatin landscape, inhibiting cell proliferation. Our findings suggest the p63-FOXK1 axis as a potential target for cancer therapy in SCCs.