SOX2 Drives Esophageal Squamous Carcinoma by Reprogramming Lipid Metabolism and Histone Acetylation Landscape (RNA-seq)

SOX2 is not only a pioneer transcription factor with critical roles in stem cell function and cell reprogramming but also a potent initiating oncodriver for a multitude of squamous cancers. How SOX2 exerts a potent oncogenic activity in squamous lineage is largely unknown. Here we uncovered a unique role of SOX2 in driving global histone acetylation and demonstrated that SOX2 is required for the formation of about half of the super-enhancers in esophageal squamous cancer cells (ESCCs). Combined metabolic, chromatin and transcriptional analysis revealed at least two mechanisms by which SOX2 drives histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and program fatty acid metabolism, which channels acetyl-CoA to histone acetylation by promoting the expression of multiple genes in fatty acid -oxidation and by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5) involved in fatty acid synthesis. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis and enhanced histone acetylation, whereas overexpression of ACSL5 resulted in lipid accumulation, histone hypoacetylation, and tumor growth inhibition. Finally, we showed that SOX2 expression correlates negatively with ACSL5 and positively with histone acetylation in clinical esophageal squamous tumors. Altogether, our study uncovers a role of SOX2 in reprogramming lipid metabolism and driving histone hyperacetylation and super-enhancer function, providing new mechanistic insights of SOX2 acting as a potent oncodriver.