SOX2 Reprograms Cellular Metabolism And Histone Modifications In Esophagus Squamous Cell Carcinoma

Esophagus carcinoma is a common digestive system cancer and can be divided into adenocarcinoma(EA)and squamous cell carcinoma(ESCC).Squamous cell carcinoma is more prevail in East-Asia countries especially in China.Through multiple large scale genomic sequencing,previous studies have identified SOX2 gene genomic amplification and consequent SOX2 overexpression in 10-20% ESCC patients.However little is known about the role of SOX2 in ESCC.In this study we first investigated if SOX2 overexpression in ESCC also involved regulation of SOX2 protein stability.We demonstrated that,as observed in mouse embryonic stem cells,SOX2 is stabilized by AKT in multiple ESCC cells with SOX2 gene amplification.Interestingly,by comparing different ESCC cell lines,we observed a positive correlation between the levels of SOX2 and histone acetylation.By knockdown and overexpression experiments we demonstrated that SOX2 regulates histone and non-histone acetylation levels in ESCC cells.Mechanistic studies revealed that SOX2 controls histone acetylation through at least three aspects:(1)SOX2 positively regulates the expression of several lysine acetyltransferases(KATs)expression;(2)SOX2 positively regulates ACSS2 expression,which presumably leads to increased production of acetyl-coA;(3)SOX2 inhibits ASCL5 expression,which reduces the acetyl-coA consumption due to fatty acids synthesis.Together this combinatorial effect of SOX2 on gene expression leads to reprogramming of ESCC metabolism and histone acetylation.We further confirmed by immunohistochemistry that there is a positive correlation in ESCC samples between SOX2 expression and histone acetylation.Finally,we also observed that an increased SOX2 expression correlated with an increased histone acetylation in a skin squamous cell carcinoma mice model.Altogether our data above demonstrate that SOX2 overexpression in ESCC leads to reprogramming of cancer cell metabolism and histone modification.In this thesis we have investigated gene expression deregulated by SOX2 overexpression in ESCC and discovered that SOX2 has capacity to reprogram cell metabolism and histone modification.Our study has provided novel insight into a subset of ESCC with SOX2 overexpression and suggests that AKT inhibitor or inhibition of histone acetylation may be the potential therapeutic approach for this subset of tumors.