Cisplatin-based cytotoxic chemotherapy is considered to be the first-line therapy for advanced bladder cancer (BC), but resistance to cisplatin limits its antitumor effect. Fibroblast growth factor receptor 3 (FGFR3) has been reported to contribute to the progression and cisplatin resistance of BC. Meanwhile, chromobox protein homologue 7 (CBX7) was reported to inhibit BC progression. And our previous RNA-seq data on CBX7 (GSE185630) suggested that CBX7 might repress FGFR3, but the underlying mechanism and other cancer-related functions of CBX7 are still unknown.
Silico analysis of RNA-seq data to identify the upstream regulators and downstream target genes of CBX7. The western blot analysis, quantitative real-time PCR (RT-qPCR), chromatin immunoprecipitation (ChIP)-qPCR analysis, CCK-8 assay, and nude mice xenograft models were used to confirm the enhancer of zeste homologue (EZH2)/CBX7/ FGFR3 axis.
In this study, we first showed that CBX7 is downregulated in BC. Then, we revealed that EZH2 represses CBX7 expression by increasing H3K27me3 in BC cells. Moreover, we demonstrated that CBX7 directly downregulates FGFR3 expression and sensitises BC cells to cisplatin treatment by inactivating the phosphatidylinositol 3-kinase (PI3K)-(RAC-alpha serine/threonine-protein kinase) AKT signalling pathway.
These results suggest that CBX7 is an ideal candidate to overcome cisplatin resistance in BC.
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The datasets used and/or analysed during this study are available from the corresponding authors upon reasonable request.
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This work was supported by grants from the Changsha Municipal Natural Science Foundation (No. kq2014236, BY).
The authors declare no competing interests.
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The study was conducted in accordance with the principles of the Declaration of Helsinki principles. It was approved by the Animal Use and Care Committees at the Second Xiangya Hospital, Central South University.
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Ren, J., Yu, H., Li, W. et al. Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02058-0