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88 reviewsSOX2 is a potent oncodriver for various squamous cancers, but the underlyingmechanism is largely unknown. Here we uncover a role of SOX2 in promotingglobal histone acetylation in esophageal squamous cancer cells (ESCCs).Mechanistic studies reveal that SOX2 promotes global histone acetylation inan AKT-independent manner, and does so by promoting histone acetylation atboth SOX2 binding and non-SOX2 binding sites, and accounts for the formation of about half of the super-enhancers. Combined metabolic and transcriptional analyses reveal two mechanisms by which SOX2 enhances globalhistone acetylation: promoting the expression of multiple histone acetyltransferases and reducing acetyl-CoA consuming fatty acid synthesis in part byrepressing the expression of ACSL5. Finally, SOX2 expression correlatesnegatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 inreprogramming lipid metabolism and driving histone hyperacetylation andsuper-enhancer function, providing mechanistic insights of SOX2 acting as apotent oncodriver.
