CBX2 promotes cisplatin resistance in ovarian cancer via SIAH2-mediated β-catenin stabilization and ATG9B-dependent autophagy activation.

BACKGROUND: Platinum-based chemotherapy is the first-line therapeutic strategy for ovarian cancer (OC), and resistance to it adversely affects most OC patients. CBX2 plays an essential role in cancer progression and is widely thought to be involved in cisplatin (DDP) resistance. This study aimed to investigate the molecular mechanism of CBX2 in DDP resistance in OC. MATERIALS AND METHODS: The human normal ovarian epithelial cell line (IOSE80) and OC cell lines (SK-OV-3 and OVcar3) were used. The functions of CBX2 and ATG9B were explored by transfecting overexpression and silencing plasmids into OC cells. Drug-resistant DDP OC cell lines were established. Real-time quantitative PCR (qPCR), Western blotting, and immunofluorescence (IF) analysis were conducted to evaluate the molecular expression at the mRNA and protein levels. The Cell Counting Kit-8 (CCK-8) assay measured the IC(50) value of cells under DDP treatment. Flow cytometry was used to determine cell apoptosis, and a colony formation assay was used to measure cell proliferation. A co-immunoprecipitation (Co-IP) assay evaluated the binding relationship between SIAH2 and β-catenin. RESULTS: CBX2 was highly expressed in OC and was associated with DDP resistance. Besides, CBX2 overexpression enhanced DDP resistance and autophagy in OC cells. As expected, CBX2 silencing suppressed autophagy and DDP resistance in OC cells. Mechanistically, CBX2 stabilized β-catenin by inhibiting ubiquitin-mediated degradation. Inhibiting the Wnt/β-catenin pathway suppressed CBX2-induced autophagy and decreased DDP resistance in OC cells. Activating the Wnt/β-catenin pathway promoted CBX2-induced autophagy and increased DDP resistance in OC cells. ATG9B mediated CBX2-induced autophagy and DDP resistance. Finally, ATG9B inhibition rescued the effects of CBX2-mediated autophagy and DDP resistance. CONCLUSION: CBX2 promotes cisplatin resistance in OC via SIAH2-mediated β-catenin stabilization and ATG9B-dependent autophagy activation. Overall, our study reveals a hitherto undocumented role of CBX2 in mediating DDP resistance, providing insights for potential therapeutic biomarkers to overcome DDP resistance in OC.