Mechanism of Helicobacter pylori-induced FOXO3a ubiquitination and degradation in gastric epithelial cells by modifying YWHAZ through B4GALT5-mediated glycosylation during gastric carcinogenesis.

BACKGROUND

Abnormal glycosylation modifications are pivotal in tumorigenesis. However, the mechanism by which Helicobacter pylori (H. pylori) infection affects glycosylation during gastric cancer (GC) progression is not well understood. This study investigated how H. pylori infection-related glycosylation contributes to GC, aiming to uncover new therapeutic targets.

METHODS

Differentially expressed glycosyltransferases were identified using lectin microarray analysis following H. pylori infection. Beta-1,4-galactosyltransferase 5 (B4GALT5) was specifically identified in both non- and H. pylori infected AGS cells, and GC tissues. The biological functions of B4GALT5 and its regulatory mechanisms in H. pylori infection-mediated GC progression were investigated in vitro and vivo.

RESULTS

B4GALT5 expression remarkedly increased in GC cells after H. pylori infection and was linked to poor clinical outcomes in patients with GC. Its overexpression reduced cellular apoptosis,and promotedmigration, and invasion, while reducing the effectiveness of chemotherapeutic drugs such as cisplatin and paclitaxel. Mechanistic investigations demonstrated that B4GALT5 directly interacts with YWHAZ, enhancing its glycosylation at the N95 site and thus strengthening its binding to FOXO3a. This subsequently led to FOXO3a degradation, preventing its nuclear translocation. In an in-situ tumor-bearing mouse model, B4GALT5 overexpression accelerated tumor growth, whereas mutating the N95 site of YWHAZ reduced this effect.

CONCLUSIONS

Our study reveals that H. pylori contribute to gastric carcinogenesis by activating the B4GALT5/YWHAZ/FOXO3a axis via specific glycosylation, suggesting YWHAZ N95 glycosylation as a potential therapeutic target for GC.