EZH2 Regulates Intestinal Inflammation and Necroptosis Through the JNK Signaling Pathway in Intestinal Epithelial Cells

Background: Inflammatory bowel disease (IBD) is a common disorder of chronic intestinal inflammation that can be caused by the disruption of intestinal immune homeostasis.

Aim: We aimed to evaluate the role of enhancer of zeste homolog 2 (EZH2) in the inflammatory response and explore the association between EZH2 and Necroptosis in human epithelial colorectal adenocarcinoma cell lines.

Methods: In both in vitro and in vivo models, expression of EZH2 in intestinal tissues was verified by histology. The expression of inflammatory cytokines in cell lines treated with EZH2 siRNA with or without stimulus was analyzed by quantitative real-time polymerase chain reaction. An intestinal Necroptosis cell model was established to elucidate whether EZH2 is involved in Necroptosis.

Results: Our present data indicated that EZH2 expression was decreased in in vitro and in vivo models and in patients with inflammatory bowel disease. EZH2 downregulation increased the expression of inflammatory factors, including TNF-α, IL-8, IL-17, CCL5, and CCL20 in a Caco-2 cell model. The JNK pathway was activated with the reduction of EZH2. In the Necroptosis model, downregulation of EZH2 was detected with the upregulation of necroptotic markers RIP1 and RIP3. In addition, EZH2 knockdown with siRNA increased p-JNK and p-c-Jun.

Conclusion: Our data suggest that EZH2 plays an important role in the development of intestinal inflammation and Necroptosis. Hence, EZH2 could be a potential therapeutic target for IBD.