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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The online version contains supplementary material available at https://doi.org/10.6084/m9.figshare.20514261.
References
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.
Pennathur A, Gibson MK, Jobe BA, Luketich JD. Oesophageal carcinoma. Lancet. 2013;381:400–12.
Malhotra GK, Yanala U, Ravipati A, Follet M, Vijayakumar M, Are C. Global trends in esophageal cancer. J Surg Oncol. 2017;115:564–79.
Pickens A, Orringer MB. Geographical distribution and racial disparity in esophageal cancer. Ann Thorac Surg. 2003;76:S1367–9.
Hershko DD. Oncogenic properties and prognostic implications of the ubiquitin ligase Skp2 in cancer. Cancer. 2008;112:1415–24.
Gao M, Karin M. Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli. Mol Cell. 2005;19:581–93.
Wang Z, Liu P, Inuzuka H, Wei W. Roles of F-box proteins in cancer. Nat Rev Cancer. 2014;14:233–47.
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.
MacGurn JA, Hsu PC, Emr SD. Ubiquitin and membrane protein turnover: from cradle to grave. Annu Rev Biochem. 2012;81:231–59.
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.
Zheng N, Zhou Q, Wang Z, Wei W. Recent advances in SCF ubiquitin ligase complex: clinical implications. Biochim Biophys Acta. 2016;1866:12–22.
Nalepa G, Rolfe M, Harper JW. Drug discovery in the ubiquitin-proteasome system. Nat Rev Drug Discov. 2006;5:596–613.
Ravid T, Hochstrasser M. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol. 2008;9:679–90.
Gong J, Huang Z, Huo JR. Involvement of F-box proteins in esophageal cancer (Review). Int J Oncol. 2016;48:886–94.
Gong J, Lv L, Huo J. Roles of F-box proteins in human digestive system tumors (Review). Int J Oncol. 2014;45:2199–207.
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.
Yoshida K. Characterization of estrogen-induced F-box protein FBXO45. Oncol Rep. 2005;14:531–5.
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.
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.
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.
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.
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.
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.
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.
Abshire CF, Carroll JL, Dragoi AM. FLASH protects ZEB1 from degradation and supports cancer cells’ epithelial-to-mesenchymal transition. Oncogenesis. 2016;5:e254.
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.
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.
Glynn RW, Miller N, Kerin MJ. 17q12-21 - the pursuit of targeted therapy in breast cancer. Cancer Treat Rev. 2010;36:224–9.
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.
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.
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.
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.
Hu X, Lazar MA. The CoRNR motif controls the recruitment of corepressors by nuclear hormone receptors. Nature. 1999;402:93–96.
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.
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.
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.
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.
Lin M, Wang ZW, Zhu X. FBXO45 is a potential therapeutic target for cancer therapy. Cell Death Discov. 2020;6:55.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
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 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.
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41388-022-02468-7
This article is cited by
-
FBXO28 promotes cell proliferation, migration and invasion via upregulation of the TGF-beta1/SMAD2/3 signaling pathway in ovarian cancer
BMC Cancer (2024)
-
RIG-I promotes cell proliferation in esophageal squamous cell carcinoma by facilitating p21 degradation
Medical Oncology (2023)
-
CDC20 promotes radioresistance of prostate cancer by activating Twist1 expression
Apoptosis (2023)