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.