O-GlcNAcylation enhances Reticulon 2 protein stability and its promotive effects on gastric cancer progression.

Our previous study indicated that Reticulon 2 (RTN2) was upregulated and facilitated the progression of gastric cancer. Protein O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) is a general feature during tumorigenesis, and regulates protein activity and stability through post-translational modification on serine/threonine. However, the relationship between RTN2 and O-GlcNAcylation have never been determined. In this study, we explored the influence of O-GlcNAcylation on RTN2 expression and its promotive role in gastric cancer. We found that RTN2 interacted with O-GlcNAc transferase (OGT) and was modified by O-GlcNAc. O-GlcNAcylation enhanced RTN2 protein stability via attenuating its lysosomal degradation in gastric cancer cells. Furthermore, our results demonstrated that RTN2-induced activation of ERK signalling was dependent on O-GlcNAcylation. Consistently, the stimulative effects of RTN2 on cellular proliferation and migration were abrogated by OGT inhibition. Tissue microarray with immumohistochemical staining also confirmed that the expression of RTN2 was positively correlated with the level of total O-GlcNAcylation as well as the phosphorylation level of ERK. Besides, combined RTN2 and O-GlcNAc staining intensity could improve predictive accuracy for gastric cancer patients' survival compared with each alone. Altogether, these findings suggest that O-GlcNAcylation on RTN2 was pivotal for its oncogenic functions in gastric cancer. Targeting RTN2 O-GlcNAcylation might provide new ideas for gastric cancer therapies.