ΔNp63α is a super enhancer-enriched master factor controlling the basal-to-luminal differentiation transcriptional program and gene regulatory networks in nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) originates via malignant transformation of the pseudostratified nasopharyngeal epithelium, composed of basal and luminal cells. Super enhancers (SEs) are large clusters of cis-elements involved in the regulation of gene expression through epigenetic regulatory mechanisms. In this study, we demonstrated that basal cell-specific proteins are highly expressed, whereas luminal cell proteins are downregulated in NPC, implying a perturbation of basal-to-luminal differentiation during NPC development. We characterized NPC cell models according to different molecular signatures associated with their differentiation status and found that distinct SE landscapes are tightly associated with basal or luminal-like molecular signatures in NPC cells. Furthermore, the transcription of Delta NP63 alpha, a prominent isoform of TP63, was found to be driven by SEs in NPC cells. Data from chromatin immunoprecipitation (ChIP)-sequencing showed that Delta NP63 alpha largely occupied regions of SEs associated with basal cell-specific genes. Silencing of Delta NP63 alpha led to a loss of H3K27ac occupancy at basal-type SEs and triggered a basal-to-luminal gene expression signature switch, suggesting that Delta NP63 alpha is a master factor contributing to the perturbation of luminal differentiation. Integrative transcriptomics analysis also revealed that Delta NP63 alpha acts as a core factor involved in the dysregulation of gene expression in NPC. Furthermore, Delta NP63 alpha enhanced EGF-stimulated NF-kappa B activation in NPC cells by activating SE-mediated EGFR transcription. Finally, depletion of Delta NP63 alpha in NPC cells induced robust growth inhibition of NPC cells in vitro and in vivo. Our data revealed that Delta NP63 alpha-dependent SE reprogramming contributes to the blockade of luminal differentiation and uncontrolled proliferation in NPC.