Cooperating lineage factors SOX2 and BRN2 govern the transcriptional program of the neural subtype of lung squamous cell carcinoma

Lung squamous cell carcinoma (LUSC) is one of the major subtypes of lung cancer, molecular characterization of which has not sufficiently improved its treatment strategies. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states not only during normal development but also during cancer evolution. By investigating the super-enhancer landscape of LUSC, we identified a unique ‘neural’ subtype defined by Sox2 and a neural lineage factor Brn2. Robust protein-protein interaction and genomic co-occupancy of these factors indicated their transcriptional cooperation in this ‘neural’ LUSC in contrast to the cooperation of Sox2 and p63 in the classical LUSC. Introduction of p63 expression in the ‘neural’ LUSC invoked the classical LUSC lineage accompanied by Brn2 downregulation and increased activities of ErbB/Akt and MAPK-ERK pathways. Collectively, our data demonstrate a unique LUSC lineage featured by Sox2 cooperation with Brn2 instead of p63, for which distinct therapeutic approaches may be warranted.