?Np63 executes an oncogenic program through the regulation of a common landscape of super-enhancer associated genes in non-small cell lung cancer

Distinct lung stem cells give rise to lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). ?Np63 guides development of these cells through regulation of terminal differentiation; however, its mechanistic role in lung cancer development has remained elusive. We utilized a ?Np63-specific conditional knockout mouse model and found that ?Np63 maintains lung ADC and SCC by keeping lung stem cells in quiescence. ChIP-seq analysis of lung basal cells and alveolar type 2 (AT2) cells lacking ?Np63 revealed a robust loss of activating histone marks at super enhancers of cell identity genes defining a unifying oncogenic role for ?Np63 in non-small cell lung cancer. Overall design: Basal cells and AT2 cells isolated from ?Np63fl/fl and ?Np63?/? mice were analyzed by RNA-seq and ChIP-seq.