SOX2 Drives Esophageal Squamous Carcinoma by Reprogramming Lipid Metabolism and Histone Acetylation Landscape

SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent oncogene for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered SOX2 a potent role in promoting global histone acetylation and super-enhancer formation in esophageal squamous cancer cells. Metabolic analysis revealed a role of SOX2 in suppressing fatty acid synthesis. SOX2 promotes global histone acetylation by two distinct mechanisms: stimulating the expression of a panel of histone acetyltransferases and repressing the expression of ACSL5, which down-regulates fatty acid synthesis and thus channels acetyl-CoA toward histone acetylation. Notably, we found that SOX2 enhanced histone acetylation is required for the formation of most squamous lineage-specific super-enhancers. Our findings provide new explanation for why SOX2 is a powerful cell fate reprogrammer and potent oncogene for squamous lineage cancers.