Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cellular and Molecular Biology

Downregulation of CBX7 induced by EZH2 upregulates FGFR3 expression to reduce sensitivity to cisplatin in bladder cancer

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

These results suggest that CBX7 is an ideal candidate to overcome cisplatin resistance in BC.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: CBX7 is downregulated in bladder cancer and associated with hypermethylation in its promoter region.
Fig. 2: EZH2 suppresses CBX7 expression through H3K27 methylation in BC cells.
Fig. 3: CBX7 transcriptionally represses FGFR3 expression in BC cells.
Fig. 4: CBX7 impedes the bladder cancer progression partially through FGFR3.
Fig. 5: CBX7 modulates BC cell proliferation via the FGFR3–PI3K–AKT signalling pathway.
Fig. 6: The CBX7–FGFR3 axis modulates cisplatin resistance in BC cells.

Data availability

The datasets used and/or analysed during this study are available from the corresponding authors upon reasonable request.

References

  1. Seidl C. Targets for therapy of bladder cancer. Semin Nucl Med. 2020;50:162–70.

    Article  PubMed  Google Scholar 

  2. Patel VG, Oh WK, Galsky MD. Treatment of muscle-invasive and advanced bladder cancer in 2020. CA Cancer J Clin. 2020;70:404–23.

    Article  PubMed  Google Scholar 

  3. Alifrangis C, McGovern U, Freeman A, Powles T, Linch M. Molecular and histopathology directed therapy for advanced bladder cancer. Nat Rev Urol. 2019;16:465–83.

    Article  CAS  PubMed  Google Scholar 

  4. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharm. 2014;740:364–78.

    Article  CAS  Google Scholar 

  5. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.

    Article  CAS  PubMed  Google Scholar 

  6. Lenis AT, Lec PM, Chamie K, Mshs MD. Bladder cancer: a review. J Am Med Assoc. 2020;324:1980–91.

    Article  CAS  Google Scholar 

  7. Necchi A, Anichini A, Raggi D, Briganti A, Massa S, Luciano R, et al. Pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive urothelial bladder carcinoma (PURE-01): an open-label, single-arm, phase II study. J Clin Oncol. 2018;36:3353–60.

    Article  CAS  PubMed  Google Scholar 

  8. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell. 2017;171:540–56.e525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kardoust Parizi M, Margulis V, Lotan Y, Mori K, Shariat SF. Fibroblast growth factor receptor: a systematic review and meta-analysis of prognostic value and therapeutic options in patients with urothelial bladder carcinoma. Urol Oncol. 2021;39:409–21.

    Article  CAS  PubMed  Google Scholar 

  10. van Rhijn BWG, Mertens LS, Mayr R, Bostrom PJ, Real FX, Zwarthoff EC, et al. FGFR3 mutation status and FGFR3 expression in a large bladder cancer cohort treated by radical cystectomy: implications for anti-FGFR3 treatment?(dagger). Eur Urol. 2020;78:682–7.

    Article  PubMed  Google Scholar 

  11. Xie X, Lin J, Zhong Y, Fu M, Tang A. FGFR(3S249C) mutation promotes chemoresistance by activating Akt signaling in bladder cancer cells. Exp Ther Med. 2019;18:1226–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hong JH, Tong ZJ, Wei TE, Lu YC, Huang CY, Huang CY, et al. Cigarette smoke containing acrolein contributes to cisplatin resistance in human bladder cancers through the regulation of HER2 pathway or FGFR3 pathway. Mol Cancer Ther. 2022;21:1010–9.

    Article  CAS  PubMed  Google Scholar 

  13. Montazeri K, Bellmunt J. Erdafitinib for the treatment of metastatic bladder cancer. Expert Rev Clin Pharm. 2020;13:1–6.

    Article  CAS  Google Scholar 

  14. Ni SJ, Zhao LQ, Wang XF, Wu ZH, Hua RX, Wan CH, et al. CBX7 regulates stem cell-like properties of gastric cancer cells via p16 and AKT-NF-kappaB-miR-21 pathways. J Hematol Oncol. 2018;11:17.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Huang Z, Yan Y, Zhu Z, Liu J, He X, Dalangood S, et al. CBX7 suppresses urinary bladder cancer progression via modulating AKR1B10-ERK signaling. Cell Death Dis. 2021;12:537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang Z, Liu J, Yang J, Yan Y, Yang C, He X, et al. PDE4B induces epithelial-to-mesenchymal transition in bladder cancer cells and is transcriptionally suppressed by CBX7. Front Cell Dev Biol. 2021;9:783050.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Liu W, Wang H, Jian C, Li W, Ye K, Ren J, et al. The RNF26/CBX7 axis modulates the TNF pathway to promote cell proliferation and regulate sensitivity to TKIs in ccRCC. Int J Biol Sci. 2022;18:2132–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ren W, Ren J, Zhang N, Liu X, Deng Y, Jiang Y, et al. CBX7 represses the POU2F2 to inhibit the PD-L1 expression and regulate the immune response in bladder cancer. Biochem Biophys Res Commun. 2022;613:12–18.

    Article  CAS  PubMed  Google Scholar 

  19. Jin X, Ding D, Yan Y, Li H, Wang B, Ma L, et al. Phosphorylated RB promotes cancer immunity by inhibiting NF-kappaB activation and PD-L1 expression. Mol Cell. 2019;73:22–35.e26.

    Article  CAS  PubMed  Google Scholar 

  20. Yi L, Wang H, Li W, Ye K, Xiong W, Yu H, et al. The FOXM1/RNF26/p57 axis regulates the cell cycle to promote the aggressiveness of bladder cancer. Cell Death Dis. 2021;12:944.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Oki S, Ohta T, Shioi G, Hatanaka H, Ogasawara O, Okuda Y, et al. ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data. EMBO Rep. 2018;19:e46255.

  22. Zhang T, Gong Y, Meng H, Li C, Xue L. Symphony of epigenetic and metabolic regulation-interaction between the histone methyltransferase EZH2 and metabolism of tumor. Clin Epigenet. 2020;12:72.

    Article  CAS  Google Scholar 

  23. Taylor-Papadimitriou J, Burchell JM. Histone methylases and demethylases regulating antagonistic methyl marks: changes occurring in cancer. Cells. 2022;11:1113.

  24. Duan R, Du W, Guo W. EZH2: a novel target for cancer treatment. J Hematol Oncol. 2020;13:104.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tomlinson DC, Hurst CD, Knowles MA. Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene. 2007;26:5889–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Jaensch ES, Zhu J, Cochrane JC, Marr SK, Oei TA, Damle M, et al. A Polycomb domain found in committed cells impairs differentiation when introduced into PRC1 in pluripotent cells. Mol Cell. 2021;81:4677–91.e4678.

    Article  CAS  PubMed  Google Scholar 

  27. Pandith AA, Shah ZA, Siddiqi MA. Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer. Urol Oncol. 2013;31:398–406.

    Article  CAS  PubMed  Google Scholar 

  28. Mao W, Huang X, Wang L, Zhang Z, Liu M, Li Y, et al. Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression. J Exp Clin Cancer Res. 2019;38:169.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev. 2004;30:193–204.

    Article  PubMed  Google Scholar 

  30. Witjes JA, Bruins HM, Cathomas R, Comperat EM, Cowan NC, Gakis G, et al. European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol. 2021;79:82–104.

    Article  CAS  PubMed  Google Scholar 

  31. Winograd-Katz SE, Levitzki A. Cisplatin induces PKB/Akt activation and p38(MAPK) phosphorylation of the EGF receptor. Oncogene. 2006;25:7381–90.

    Article  CAS  PubMed  Google Scholar 

  32. Zhao J, Tan W, Zhang L, Liu J, Shangguan M, Chen J, et al. FGFR3 phosphorylates EGFR to promote cisplatin-resistance in ovarian cancer. Biochem Pharm. 2021;190:114536.

    Article  CAS  PubMed  Google Scholar 

  33. Chen L, Zhang Y, Yin L, Cai B, Huang P, Li X, et al. Fibroblast growth factor receptor fusions in cancer: opportunities and challenges. J Exp Clin Cancer Res. 2021;40:345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bae JH, Schlessinger J. Asymmetric tyrosine kinase arrangements in activation or autophosphorylation of receptor tyrosine kinases. Mol Cells. 2010;29:443–8.

    Article  CAS  PubMed  Google Scholar 

  35. Nakamura IT, Kohsaka S, Ikegami M, Ikeuchi H, Ueno T, Li K, et al. Comprehensive functional evaluation of variants of fibroblast growth factor receptor genes in cancer. NPJ Precis Oncol. 2021;5:66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kacew A, Sweis RF. FGFR3 alterations in the era of immunotherapy for urothelial bladder cancer. Front Immunol. 2020;11:575258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Al-Obaidy KI, Cheng L. Fibroblast growth factor receptor (FGFR) gene: pathogenesis and treatment implications in urothelial carcinoma of the bladder. J Clin Pathol. 2021;74:491–5.

    Article  CAS  PubMed  Google Scholar 

  38. Jing W, Wang G, Cui Z, Xiong G, Jiang X, Li Y, et al. FGFR3 destabilizes PD-L1 via NEDD4 to control T-cell-mediated bladder cancer immune surveillance. Cancer Res. 2022;82:114–29.

    Article  CAS  PubMed  Google Scholar 

  39. di Martino E, Alder O, Hurst CD, Knowles MA. ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer. Sci Rep. 2019;9:5740.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Iyer G, Milowsky MI. Fibroblast growth factor receptor-3 in urothelial tumorigenesis. Urol Oncol. 2013;31:303–11.

    Article  CAS  PubMed  Google Scholar 

  41. Chen L, Xiong Y, Yan C, Zhou W, Endo Y, Xue H, et al. LncRNA KCNQ1OT1 accelerates fracture healing via modulating miR-701-3p/FGFR3 axis. FASEB J. 2020;34:5208–22.

    Article  CAS  PubMed  Google Scholar 

  42. Long X, Shi Y, Ye P, Guo J, Zhou Q, Tang Y. MicroRNA-99a suppresses breast cancer progression by targeting FGFR3. Front Oncol. 2019;9:1473.

    Article  PubMed  Google Scholar 

  43. Jing P, Zhao N, Xie N, Ye M, Zhang Y, Zhang Z, et al. miR-24-3p/FGFR3 signaling as a novel axis is involved in epithelial-mesenchymal transition and regulates lung adenocarcinoma progression. J Immunol Res. 2018;2018:2834109.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zheng C, Lin X, Xu X, Wang C, Zhou J, Gao B, et al. Suppressing UPR-dependent overactivation of FGFR3 signaling ameliorates SLC26A2-deficient chondrodysplasias. EBioMedicine. 2019;40:695–709.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Pallante P, Forzati F, Federico A, Arra C, Fusco A. Polycomb protein family member CBX7 plays a critical role in cancer progression. Am J Cancer Res. 2015;5:1594–601.

    PubMed  PubMed Central  Google Scholar 

  46. Mansueto G, Forzati F, Ferraro A, Pallante P, Bianco M, Esposito F, et al. Identification of a new pathway for tumor progression: microRNA-181b up-regulation and CBX7 down-regulation by HMGA1 protein. Genes Cancer. 2010;1:210–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hannafon BN, Sebastiani P, de las Morenas A, Lu J, Rosenberg CL. Expression of microRNA and their gene targets are dysregulated in preinvasive breast cancer. Breast Cancer Res. 2011;13:R24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Jiang Z, Guo J, Xiao B, Miao Y, Huang R, Li D, et al. Increased expression of miR-421 in human gastric carcinoma and its clinical association. J Gastroenterol. 2010;45:17–23.

    Article  CAS  PubMed  Google Scholar 

  49. Xie D, Shang C, Zhang H, Guo Y, Tong X. Up-regulation of miR-9 target CBX7 to regulate invasion ability of bladder transitional cell carcinoma. Med Sci Monit. 2015;21:225–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang Z, Zhang R, Ge Y, Qin X, Kang X, Wang Y, et al. Somatic FGFR3 mutations distinguish a subgroup of muscle-invasive bladder cancers with response to neoadjuvant chemotherapy. EBioMedicine. 2018;35:198–203.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Reed MF, Zagorski WA, Knudsen ES. RB activity alters checkpoint response and chemosensitivity in lung cancer lines. J Surg Res. 2007;142:364–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vinall RL, Ripoll AZ, Wang S, Pan CX, deVere White RW. MiR-34a chemosensitizes bladder cancer cells to cisplatin treatment regardless of p53-Rb pathway status. Int J Cancer. 2012;130:2526–38.

    Article  CAS  PubMed  Google Scholar 

  54. Liu X, Sun K, Wang H, Dai Y. Knockdown of retinoblastoma protein may sensitize glioma cells to cisplatin through inhibition of autophagy. Neurosci Lett. 2016;620:137–42.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the Changsha Municipal Natural Science Foundation (No. kq2014236, BY).

Author information

Authors and Affiliations

Authors

Contributions

JR: methodology; WL: methodology; HY: conceptualisation; XJ: project administration, investigation, writing—original draft and writing—review and editing; BY: investigation and project administration.

Corresponding authors

Correspondence to Xin Jin or Bin Yan.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Consent to publish

All subjects have written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41416-022-02058-0

Search

Quick links