CBX2 and EZH2 cooperatively contribute to 5-Fu resistance in gastric cancer by suppressing ferroptosis via trimethylation of H3k27

Background and objective

Chromobox 2 (CBX2) plays a pivotal role in the malignant phenotypes of several cancers, which has been found to up-regulated in gastric cancer (GC). This study aimed to investigate the specific function and underlying mechanism of CBX2 in GC.

Methods

The potential role of CBX2 in GC was uncovered based on online bioinformatic analysis. The protein and mRNA expression levels were assessed by immunohistochemistry, qRT-PCR, and western blot. Using parental and the corresponding resistant GC cell lines, the effect and mechanism of CBX2 on 5-Fu resistance were explored by cell transfection technique, CCK-8 kit, colony formation assay, flow cytometry, the commercial kit, as well as co-IP. Xenograft tumor nude mice models were applied for in vivo assay.

Results

The expression of CBX2 was up-regulated in tumor tissues of GC patients and positively correlated with chemo-resistance, as well as that of EZH2. Knockdown of CBX2 resensitized 5-Fu resistant GC cells to 5-Fu while overexpressing CBX2 enhance GC cells against 5-Fu via the regulation of ferroptosis. In vivo experiments demonstrated that CBX2 overexpression enhanced 5-Fu sensitivity in tumors. Mechanically, CBX2 and EZH2 cooperatively suppressed ferroptosis in GC cells by inducing trimethylation of H3k27 (H3k27me3). Suppressing EZH2 blocked the inductive effect of CBX2 overexpression on 5-FU sensitivity of GC cells and reduced ferroptosis and H3k27me3 levels in CBX2 overexpressed GC cells.

Conclusion

CBX2/EZH2 cooperatively confers 5-FU resistance in GC cells through suppressing ferroptosis via H3k27me3, which may lead to a promising therapeutic strategy for GC.