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

ABSTRACT:

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.

INSTRUMENT(S): Liquid Chromatography MS - alternating - reverse phase

PROVIDER: MTBLS7120 | MetaboLights | 2025-08-07

REPOSITORIES: MetaboLights

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			Action	DRS
	BLK-neg-ddms.raw	Raw
	BLK-pos-ddms.raw	Raw
	BLK3_220720095557.raw	Raw
	OE-ACSL5_1.raw	Raw
	OE-ACSL5_2.raw	Raw

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

Project description: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.

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

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

Project description: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.

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