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Fbxo45 promotes the malignant development of esophageal squamous cell carcinoma by targeting GGNBP2 for ubiquitination and degradation

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common and deadly cancers. Fbxo45, a substrate recognition subunit of E3 ligase, is critically involved in tumorigenesis and tumor progression. However, the function of Fbxo45 and the underlying mechanisms have not been elucidated in ESCC. We used cellular and molecular methods to explore the molecular basis of Fbxo45-mediated ESCC development. We found that ectopic overexpression of Fbxo45 promoted the growth of Kyse-150, Kyse30 and ECA-109 cells and inhibited the apoptosis. Moreover, overexpression of Fbxo45 promoted the migration and invasion of ESCC cells. Consistently, knockdown of Fbxo45 exhibited the opposite effects on ESCC cells. Mechanistically, we observed that Fbxo45 binds to GGNBP2 via its SPRY domain and targets GGNBP2 for ubiquitination and degradation. GGNBP2 overexpression exhibited anticancer activity in ESCC cells. Furthermore, Fbxo45 exerted its functions by regulating GGNBP2 stability in ESCC cells. Notably, overexpression of Fbxo45 facilitated tumor growth in mice. Strikingly, Fbxo45 was highly expressed in ESCC tissues, and GGNBP2 had a lower expression in ESCC specimens. High expression of Fbxo45 and low expression of GGNBP2 were associated with poor prognosis in ESCC patients. Fbxo45 was negatively correlated with GGNBP2 expression in ESCC tissues. Therefore, Fbxo45 serves as an oncoprotein to promote ESCC tumorigenesis by targeting the stability of the tumor suppressor GGNBP2 in ESCC.

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Fig. 1: Fbxo45 promotes the proliferation and inhibits the apoptosis of ESCC cells.
Fig. 2: Fbxo45 enhances ESCC cell migration and invasion.
Fig. 3: Fbxo45 regulates GGNBP2 stability via ubiquitinated degradation.
Fig. 4: GGNBP2 inhibits proliferation and increases of apoptosis.
Fig. 5: GGNBP2 reduces the migration and invasion of ESCC cells.
Fig. 6: Fbxo45 exerts oncogenic functions via regulation of GGNBP2 expression.
Fig. 7: Fbxo45 promotes ESCC tumorigenesis.

Data availability

The online version contains supplementary material available at https://doi.org/10.6084/m9.figshare.20514261.

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.

    Article  Google Scholar 

  2. Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.

    Article  PubMed  Google Scholar 

  3. Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in esophageal cancer. J Surg Oncol. 2017;115:564–79.

    Article  PubMed  Google Scholar 

  4. Pickens A, Orringer MB. Geographical distribution and racial disparity in esophageal cancer. Ann Thorac Surg. 2003;76:S1367–9.

    Article  PubMed  Google Scholar 

  5. Hershko DD. Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer. 2008;112:1415–24.

    Article  CAS  PubMed  Google Scholar 

  6. Gao M, Karin M. Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli. Mol Cell. 2005;19:581–93.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Z, Liu P, Inuzuka H, Wei W. Roles of F-box proteins in cancer. Nat Rev Cancer. 2014;14:233–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lin M, Xu Y, Gao Y, Pan C, Zhu X, Wang ZW. Regulation of F-box proteins by noncoding RNAs in human cancers. Cancer Lett. 2019;466:61–70.

    Article  CAS  PubMed  Google Scholar 

  9. MacGurn JA, Hsu PC, Emr SD. Ubiquitin and membrane protein turnover: from cradle to grave. Annu Rev Biochem. 2012;81:231–59.

    Article  CAS  PubMed  Google Scholar 

  10. Ciechanover A. Intracellular protein degradation: From a vague idea thru the lysosome and the ubiquitin-proteasome system and onto human diseases and drug targeting. Best Pract Res Clin Haematol. 2017;30:341–55.

    Article  PubMed  Google Scholar 

  11. Zheng N, Zhou Q, Wang Z, Wei W. Recent advances in SCF ubiquitin ligase complex: clinical implications. Biochim Biophys Acta. 2016;1866:12–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Nalepa G, Rolfe M, Harper JW. Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov. 2006;5:596–613.

    Article  CAS  PubMed  Google Scholar 

  13. Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol. 2008;9:679–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gong J, Huang Z, Huo JR. Involvement of F-box proteins in esophageal cancer (Review). Int J Oncol. 2016;48:886–94.

    Article  CAS  PubMed  Google Scholar 

  15. Gong J, Lv L, Huo J. Roles of F-box proteins in human digestive system tumors (Review). Int J Oncol. 2014;45:2199–207.

    Article  CAS  PubMed  Google Scholar 

  16. Gong J, Cao J, Liu G, Huo JR. Function and mechanism of F-box proteins in gastric cancer (Review). Int J Oncol. 2015;47:43–50.

    Article  CAS  PubMed  Google Scholar 

  17. Yoshida K. Characterization of estrogen-induced F-box protein FBXO45. Oncol Rep. 2005;14:531–5.

    CAS  PubMed  Google Scholar 

  18. Tada H, Okano HJ, Takagi H, Shibata S, Yao I, Matsumoto M, et al. Fbxo45, a novel ubiquitin ligase, regulates synaptic activity. J Biol Chem. 2010;285:3840–9.

    Article  CAS  PubMed  Google Scholar 

  19. Saiga T, Fukuda T, Matsumoto M, Tada H, Okano HJ, Okano H, et al. Fbxo45 forms a novel ubiquitin ligase complex and is required for neuronal development. Mol Cell Biol. 2009;29:3529–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tang X, Fang F, Yang J, Zheng X, Fan M, Wang L, et al. Association study reveals one susceptibility locus with vitiligo in the Chinese Han population. Genet Test Mol Biomark. 2019;23:791–6.

    Article  CAS  Google Scholar 

  21. Wu L, Yu K, Chen K, Zhu X, Yang Z, Wang Q, et al. Fbxo45 facilitates pancreatic carcinoma progression by targeting USP49 for ubiquitination and degradation. Cell Death Dis. 2022;13:231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen X, Sahasrabuddhe AA, Szankasi P, Chung F, Basrur V, Rangnekar VM, et al. Fbxo45-mediated degradation of the tumor-suppressor Par-4 regulates cancer cell survival. Cell Death Differ. 2014;21:1535–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Peschiaroli A, Scialpi F, Bernassola F, Pagano M, Melino G. The F-box protein FBXO45 promotes the proteasome-dependent degradation of p73. Oncogene. 2009;28:3157–66.

    Article  CAS  PubMed  Google Scholar 

  24. Richter KT, Kschonsak YT, Vodicska B, Hoffmann I. FBXO45-MYCBP2 regulates mitotic cell fate by targeting FBXW7 for degradation. Cell Death Differ. 2020;27:758–72.

    Article  CAS  PubMed  Google Scholar 

  25. Abshire CF, Carroll JL, Dragoi AM. FLASH protects ZEB1 from degradation and supports cancer cells’ epithelial-to-mesenchymal transition. Oncogenesis. 2016;5:e254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lan ZJ, Hu Y, Zhang S, Li X, Zhou H, Ding J, et al. GGNBP2 acts as a tumor suppressor by inhibiting estrogen receptor α activity in breast cancer cells. Breast Cancer Res Treat. 2016;158:263–76.

    Article  CAS  PubMed  Google Scholar 

  27. Plummer SJ, Paris MJ, Myles J, Tubbs R, Crowe J, Casey G. Four regions of allelic imbalance on 17q12-qter associated with high-grade breast tumors. Genes Chromosomes Cancer. 1997;20:354–62.

    Article  CAS  PubMed  Google Scholar 

  28. Glynn RW, Miller N, Kerin MJ. 17q12-21 - the pursuit of targeted therapy in breast cancer. Cancer Treat Rev. 2010;36:224–9.

    Article  CAS  PubMed  Google Scholar 

  29. Levin AM, Machiela MJ, Zuhlke KA, Ray AM, Cooney KA, Douglas JA. Chromosome 17q12 variants contribute to risk of early-onset prostate cancer. Cancer Res. 2008;68:6492–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhu Z, Lou C, Zheng Z, Zhu R, Tian S, Xie C, et al. ZFP403, a novel tumor suppressor, inhibits the proliferation and metastasis in ovarian cancer. Gynecologic Oncol. 2017;147:418–25.

    Article  CAS  Google Scholar 

  31. Yin F, Liu L, Liu X, Li G, Zheng L, Li D, et al. Downregulation of tumor suppressor gene ribonuclease T2 and gametogenetin binding protein 2 is associated with drug resistance in ovarian cancer. Oncol Rep. 2014;32:362–72.

    Article  CAS  PubMed  Google Scholar 

  32. Cino EA, Choy WY, Karttunen M. Characterization of the free state ensemble of the CoRNR Box motif by molecular dynamics simulations. J Phys Chem B. 2016;120:1060–8.

    Article  CAS  PubMed  Google Scholar 

  33. Hu X, Lazar MA. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature. 1999;402:93–96.

    Article  CAS  PubMed  Google Scholar 

  34. Liu J, Liu L, Yagüe E, Yang Q, Pan T, Zhao H, et al. GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation. Breast cancer Res Treat. 2019;174:65–78.

    Article  CAS  PubMed  Google Scholar 

  35. Li S, Moore AK, Zhu J, Li X, Zhou H, Lin J, et al. Ggnbp2 is essential for pregnancy success via regulation of mouse trophoblast stem cell proliferation and differentiation. Biol Reprod. 2016;94:41.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Zhan A, Lei B, Wu H, Wen Y, Zheng L, Wang S, et al. GGNBP2 suppresses the proliferation, invasion, and migration of human glioma cells. Oncol Res. 2017;25:831–42.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Guan R, Wen XY, Wu J, Duan R, Cao H, Lam S, et al. Knockdown of ZNF403 inhibits cell proliferation and induces G2/M arrest by modulating cell-cycle mediators. Mol Cell Biochem. 2012;365:211–22.

    Article  CAS  PubMed  Google Scholar 

  38. Lin M, Wang ZW, Zhu X. FBXO45 is a potential therapeutic target for cancer therapy. Cell Death Discov. 2020;6:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kogure N, Yokobori T, Ogata K, Altan B, Mochiki E, Ohno T, et al. Low expression of FBXO45 is associated with gastric cancer progression and poor prognosis. Anticancer Res. 2017;37:191–6.

    Article  CAS  PubMed  Google Scholar 

  40. Wang K, Qu X, Liu S, Yang X, Bie F, Wang Y, et al. Identification of aberrantly expressed F-box proteins in squamous-cell lung carcinoma. J Cancer Res Clin Oncol. 2018;144:1509–21.

    Article  CAS  PubMed  Google Scholar 

  41. Xu M, Zhu C, Zhao X, Chen C, Zhang H, Yuan H, et al. Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors. Oncotarget. 2015;6:979–94.

    Article  PubMed  Google Scholar 

  42. Salat D, Winkler A, Urlaub H, Gessler M. Hey bHLH proteins interact with a FBXO45 containing SCF ubiquitin ligase complex and induce its translocation into the nucleus. PloS One. 2015;10:e0130288.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, et al. m(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019;18:87.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Kim HY, Kim YM, Hong S. DNAJB9 suppresses the metastasis of triple-negative breast cancer by promoting FBXO45-mediated degradation of ZEB1. Cell Death Dis. 2021;12:461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cheng L, Wang Q, Tao X, Qin Y, Wu Q, Zheng D, et al. FOXM 1 induces Vasculogenic mimicry in esophageal cancer through beta-catenin /Tcf4 signaling. Diagnostic Pathol. 2020;15:14.

    Article  CAS  Google Scholar 

  46. Xia J, Cheng L, Mei C, Ma J, Shi Y, Zeng F, et al. Genistein inhibits cell growth and invasion through regulation of miR-27a in pancreatic cancer cells. Curr Pharm Des. 2014;20:5348–53.

    Article  CAS  PubMed  Google Scholar 

  47. Liu J, Liu L, Yague E, Yang Q, Pan T, Zhao H, et al. GGNBP2 suppresses triple-negative breast cancer aggressiveness through inhibition of IL-6/STAT3 signaling activation. Breast Cancer Res Treat. 2019;174:65–78.

    Article  CAS  PubMed  Google Scholar 

  48. Xia J, Duan Q, Ahmad A, Bao B, Banerjee S, Shi Y, et al. Genistein inhibits cell growth and induces apoptosis through up-regulation of miR-34a in pancreatic cancer cells. Curr Drug targets. 2012;13:1750–6.

    Article  CAS  PubMed  Google Scholar 

  49. Xu Y, Chen X, Pan S, Wang ZW, Zhu X. TM7SF2 regulates cell proliferation and apoptosis by activation of C-Raf/ERK pathway in cervical cancer. Cell Death Discov. 2021;7:299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Yang Q, Huang J, Wu Q, Cai Y, Zhu L, Lu X, et al. Acquisition of epithelial-mesenchymal transition is associated with Skp2 expression in paclitaxel-resistant breast cancer cells. Br J Cancer. 2014;110:1958–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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QW, LW conceived the work, performed the experiments, analyzed the data and wrote the manuscript. RC, JG, YQ performed the experiments and analyzed the data. LM, DC, SW analyzed the data. JM, YT, edited the manuscript and viewed the study. ZW wrote the manuscript, and critically viewed and supervised the study.

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Correspondence to Yisheng Tao, Jia Ma or Zhi-wei Wang.

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Wang, Q., Wu, L., Cao, R. et al. Fbxo45 promotes the malignant development of esophageal squamous cell carcinoma by targeting GGNBP2 for ubiquitination and degradation. Oncogene 41, 4795–4807 (2022). https://doi.org/10.1038/s41388-022-02468-7

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