Abstract 859: Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma

Abstract

Abstract Epithelial-mesenchymal transition (EMT) is a developmental program, which is associated with tumor progression and metastasis. Here we investigated the DNA methylation and histone modifications in the regulation of EMT in esophageal squamous cell carcinoma (ESCC). The RNA-Seq analysis identified a total of 6150 differentially expressed genes (3423 up-regulated and 2727 down-regulated). The GO terms showed that these genes belonged to several molecular functions and biological pathways. The abnormal expression of key EMT genes, some of Sox family genes and EZH2 significantly related to patient survival. The MeDIP-Seq analysis identified differentially methylated regions (DMRs) on the whole genome level with focal hypermethylation and widespread global DNA hypomethylation. The gene ontology analysis showed that the DMRs related genes belonged to several different ontological domains, such as EMT progression, cell cycle, adhesion, proliferation, and apoptosis. The results of the bisulfite-sequencing confirmed the EMT gene DMRs identified by MeDIP-Seq. However, further analyses showed that the EMT gene DMRs only related to gene expression, but not the patient survival. ChIP-Seq was then performed to observe the relationship between histone methylation and gene expression. A total of 295 genes were found to correlate with H3K27 tri-methylation (H3K27me3) , and a certain number of key EMT genes, such as ZEB1/2,AREG, GATA4,and CDH8 were identified. Further study showed that Ezh2-mediated H3K27me3 regulate the expression of key EMT genes. Ablation of Ezh2 expression prevents EMT, whereas forced expression of Ezh2 restores EMT. Sox4 gene could directly regulate Ezh2 expression, tri-methylated H3K27me3 for EMT gene repression. Taken together, our results suggest that both of the DNA methylation and H3K27me3 modification involved in the regulation of EMT in ESCC. Sox4-Ezh2-mediated H3K27me3 marks associate with key EMT gene regulation, representing an important epigenetic EMT signature. Note: This abstract was not presented at the meeting. Citation Format: Chen Chen, Ming Zhao, Xiaojie Huang, Xiang Wang, Wenliang Liu, Mingjiu Chen, Bangliang Yin, Zhi Li, Yunchang Yuan, Qianjin Lu, Fenglei Yu. Epigenetic regulation of epithelial-mesenchymal transition in esophageal squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 859. doi:10.1158/1538-7445.AM2017-859