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 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 up global histone acetylation in various esophageal squamous cancer cells (ESCCs). Chromatin immunoprecipitation sequencing (ChIP-seq) analyses demonstrated that knockdown of SOX2 in ESCC cells resulted in a global down-regulation of histone acetylation and impaired about half of the super-enhancers. We engineered an ESCC SOX2-dTAG cell line that allowed rapid degradation of SOX2, and subsequent ChIP-seq confirmed a role of SOX2 in promoting global histone acetylation, beside its role in promoting local histone acetylation at SOX2 binding regions. Combined metabolic and transcriptional analyses revealed two mechanisms by which SOX2 drives up global histone acetylation in ESCCs: promoting the expression of a panel of histone acetyltransferases and reducing long chain fatty acid synthesis/elongation at least in part by repressing the expression of long-chain acyl-CoA synthase 5 (ACSL5), which in turn channels acetyl-CoA to histone acetylation. We demonstrated that ACSL5 knockdown downregulated fatty acid synthesis/elongation 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.