Objective: Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide, and MYC overexpression has been observed in more than 40% of GC cases. Tight junctions (TJ) are intercellular junctions located at the most apical region of cell-cell contacts, and destruction of TJ can promote tumor metastasis. SETD2 is a well-known trimethyltransferase that catalyzes the formation of the H3K36me3 modification. Loss of SETD2 impairs gastric epithelial cells, promotes intestinal metamorphosis of gastric epithelial cells, and accelerates the migration and proliferation of GC cells. The purpose of this study is to explore the effect of SETD2 loss on TJ and GC.

Materials and Methods: In this study, utilizing specimens from stomach-specific oncogenic MYC overexpression and SETD2 deficiency mouse model (AMS), the author investigates the relationship between SETD2 and TJ in GC.

Results: The results demonstrate that loss of SETD2 downregulates the expression of TJ-associated genes (MAPK10, ACTR3B, and CLDN24), thereby impairing the expression of TJ-associated proteins (Claudin-1, Claudin-2, and ZO-1). Moreover, SETD2 deficiency enhances cell viability and proliferation capacity in GC cells.

Conclusions: The loss of SETD2 can disrupt the expression of TJ-related proteins and promote the tumorigenesis of gastric cancer. These findings shed light on the mechanism of tumorigenesis underlying GC and provide further theoretical support for the future development of targeted therapy against SETD2 loss in GC patients.