SOX2 drives esophageal squamous carcinoma by reprogramming lipid metabolism and histone acetylation landscape

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• SOX2 is a known oncodriver in squamous cancers.
• The precise mechanisms by which SOX2 drives cancer progression are not fully understood.

Purpose of the Study:

• To elucidate the role of SOX2 in global histone acetylation in esophageal squamous cell carcinoma (ESCC).
• To investigate the molecular mechanisms linking SOX2 to histone acetylation and cancer.
• To explore the impact of SOX2 on cellular metabolism and super-enhancer formation.

Main Methods:

• Mechanistic studies in esophageal squamous cancer cells (ESCCs).
• Analysis of SOX2 binding sites and histone acetylation patterns.
• Combined metabolic and transcriptional analyses.
• Correlation studies with clinical esophageal squamous tumor data.

Main Results:

• SOX2 promotes global histone acetylation in ESCCs through AKT-independent pathways.
• SOX2 influences acetylation at both direct binding and non-binding sites, contributing to super-enhancer formation.
• SOX2 enhances histone acetyltransferase expression and represses fatty acid synthesis by downregulating ACSL5.
• Clinical data show an inverse correlation between SOX2 and ACSL5, and a positive correlation between SOX2 and histone acetylation.

Conclusions:

• SOX2 plays a critical role in reprogramming lipid metabolism and driving histone hyperacetylation in ESCC.
• SOX2 enhances super-enhancer function, providing mechanistic insights into its role as a potent oncodriver.
• Targeting SOX2-mediated pathways may offer therapeutic strategies for squamous cancers.