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Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression

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Abstract

Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial–mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.

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The data used and analyzed in the current study are available from the corresponding author upon reasonable request.

References

  1. Morgan E, Soerjomataram I, Rumgay H, Coleman HG, Thrift AP, Vignat J, et al. The global landscape of esophageal squamous cell carcinoma and esophageal adenocarcinoma incidence and mortality in 2020 and projections to 2040: new estimates from GLOBOCAN 2020. Gastroenterology. 2022;163(3):649-58.e2. https://doi.org/10.1053/j.gastro.2022.05.054.

    Article  PubMed  Google Scholar 

  2. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet (London, England). 2018;391(10125):1023–75. https://doi.org/10.1016/s0140-6736(17)33326-3.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, et al. Molecular architecture of the inner ring scaffold of the human nuclear pore complex. Science (New York, NY). 2016;352(6283):363–5. https://doi.org/10.1126/science.aaf0643.

    Article  CAS  Google Scholar 

  4. Sakuma S, Raices M, Borlido J, Guglielmi V, Zhu EYS, D’Angelo MA. Inhibition of nuclear pore complex formation selectively induces cancer cell death. Cancer Discov. 2021;11(1):176–93. https://doi.org/10.1158/2159-8290.Cd-20-0581.

    Article  PubMed  CAS  Google Scholar 

  5. Bersini S, Lytle NK, Schulte R, Huang L, Wahl GM, Hetzer MW. Nup93 regulates breast tumor growth by modulating cell proliferation and actin cytoskeleton remodeling. Life Sci Alliance. 2020. https://doi.org/10.26508/lsa.201900623.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Nataraj NB, Noronha A, Lee JS, Ghosh S, Mohan Raju HR, Sekar A, et al. Nucleoporin-93 reveals a common feature of aggressive breast cancers: robust nucleocytoplasmic transport of transcription factors. Cell Rep. 2022;38(8): 110418. https://doi.org/10.1016/j.celrep.2022.110418.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Ouyang X, Hao X, Liu S, Hu J, Hu L. Expression of Nup93 is associated with the proliferation, migration and invasion capacity of cervical cancer cells. Acta Biochim Biophys Sin. 2019;51(12):1276–85. https://doi.org/10.1093/abbs/gmz131.

    Article  PubMed  CAS  Google Scholar 

  8. Lin CS, Liang Y, Su SG, Zheng YL, Yang X, Jiang N, et al. Nucleoporin 93 mediates β-catenin nuclear import to promote hepatocellular carcinoma progression and metastasis. Cancer Lett. 2022;526:236–47. https://doi.org/10.1016/j.canlet.2021.11.001.

    Article  PubMed  CAS  Google Scholar 

  9. Monwan W, Kawasaki T, Hasan MZ, Ori D, Kawai T. Identification of nucleoporin 93 (Nup93) that mediates antiviral innate immune responses. Biochem Biophys Res Commun. 2020;521(4):1077–82. https://doi.org/10.1016/j.bbrc.2019.11.035.

    Article  PubMed  CAS  Google Scholar 

  10. Lv K, Gong C, Antony C, Han X, Ren JG, Donaghy R, et al. HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis. Cell Stem Cell. 2021;28(7):1275-90.e9. https://doi.org/10.1016/j.stem.2021.02.008.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Uemoto Y, Katsuta E, Kondo N, Wanifuchi-Endo Y, Fujita T, Asano T, et al. Low HECTD1 mRNA expression is associated with poor prognosis and may be correlated with increased mitochondrial respiratory function in breast cancer. Am J Cancer Res. 2022;12(4):1593–605.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Duhamel S, Goyette MA, Thibault MP, Filion D, Gaboury L, Côté JF. The E3 ubiquitin ligase HectD1 suppresses EMT and metastasis by targeting the +TIP ACF7 for degradation. Cell Rep. 2018;22(4):1016–30. https://doi.org/10.1016/j.celrep.2017.12.096.

    Article  PubMed  CAS  Google Scholar 

  13. Wang X, De Geyter C, Jia Z, Peng Y, Zhang H. HECTD1 regulates the expression of SNAIL: Implications for epithelial-mesenchymal transition. Int J Oncol. 2020;56(5):1186–98. https://doi.org/10.3892/ijo.2020.5002.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Shimada Y, Imamura M, Wagata T, Yamaguchi N, Tobe T. Characterization of 21 newly established esophageal cancer cell lines. Cancer. 1992;69(2):277–84. https://doi.org/10.1002/1097-0142(19920115)69:2%3c277::aid-cncr2820690202%3e3.0.co;2-c.

    Article  PubMed  CAS  Google Scholar 

  15. Twarock S, Reichert C, Bach K, Reiners O, Kretschmer I, Gorski DJ, et al. Inhibition of the hyaluronan matrix enhances metabolic anticancer therapy by dichloroacetate in vitro and in vivo. Br J Pharmacol. 2019;176(23):4474–90. https://doi.org/10.1111/bph.14808.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Amin MN, Hussain MS, Sarwar MS, Rahman Moghal MM, Das A, Hossain MZ, et al. How the association between obesity and inflammation may lead to insulin resistance and cancer. Diabetes Metab Syndr. 2019;13(2):1213–24. https://doi.org/10.1016/j.dsx.2019.01.041.

    Article  PubMed  Google Scholar 

  17. Zargari S, Negahban Khameneh S, Rad A, Forghanifard MM. MEIS1 promotes expression of stem cell markers in esophageal squamous cell carcinoma. BMC Cancer. 2020;20(1):789. https://doi.org/10.1186/s12885-020-07307-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Khales SA, Mozaffari-Jovin S, Geerts D, Abbaszadegan MR. TWIST1 activates cancer stem cell marker genes to promote epithelial-mesenchymal transition and tumorigenesis in esophageal squamous cell carcinoma. BMC Cancer. 2022;22(1):1272. https://doi.org/10.1186/s12885-022-10252-9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. National Research Council Committee for the Update of the Guide for the C, Use of Laboratory A. The National Academies Collection: Reports funded by National Institutes of Health. Guide for the Care and Use of Laboratory Animals. Washington (DC): National Academies Press (US) Copyright © 2011, National Academy of Sciences. 2011.

  20. Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48(W1):W509-w14. https://doi.org/10.1093/nar/gkaa407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Yu K, Ganesan K, Tan LK, Laban M, Wu J, Zhao XD, et al. A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers. PLoS Genet. 2008;4(7): e1000129. https://doi.org/10.1371/journal.pgen.1000129.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Chen YK, Tung CW, Lee JY, Hung YC, Lee CH, Chou SH, et al. Plasma matrix metalloproteinase 1 improves the detection and survival prediction of esophageal squamous cell carcinoma. Sci Rep. 2016;6:30057. https://doi.org/10.1038/srep30057.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Ghandi M, Huang FW, Jané-Valbuena J, Kryukov GV, Lo CC, McDonald ER, et al. Next-generation characterization of the cancer cell line encyclopedia. Nature. 2019;569(7757):503–8. https://doi.org/10.1038/s41586-019-1186-3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Liu C-J, Hu F-F, Xie G-Y, Miao Y-R, Li X-W, Zeng Y, et al. GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels. Brief Bioinform. 2022. https://doi.org/10.1093/bib/bbac558.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Bairoch A. The cellosaurus, a cell-line knowledge resource. J Biomol Tech JBT. 2018;29(2):25–38. https://doi.org/10.7171/jbt.18-2902-002.

    Article  PubMed  Google Scholar 

  26. Nakagami H, Kawamura K, Sugisaka K, Sekine M, Shinmyo A. Phosphorylation of retinoblastoma-related protein by the cyclin D/cyclin-dependent kinase complex is activated at the G1/S-phase transition in tobacco. Plant Cell. 2002;14(8):1847–57. https://doi.org/10.1105/tpc.002550%JThePlantCell.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Qiao M, Shapiro P, Fosbrink M, Rus H, Kumar R, Passaniti A. Cell cycle-dependent phosphorylation of the RUNX2 transcription factor by cdc2 regulates endothelial cell proliferation. J Biol Chem. 2006;281(11):7118–28. https://doi.org/10.1074/jbc.M508162200.

    Article  PubMed  CAS  Google Scholar 

  28. Dong D, Zhang W, Xiao W, Wu Q, Cao Y, Gao X, et al. A GRN autocrine-dependent FAM135B/AKT/mTOR feedforward loop promotes esophageal squamous cell carcinoma progression. Can Res. 2021;81(4):910–22. https://doi.org/10.1158/0008-5472.Can-20-0912.

    Article  CAS  Google Scholar 

  29. Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998;331(1):299–308. https://doi.org/10.1042/bj3310299.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci USA. 1998;95(19):11211–6. https://doi.org/10.1073/pnas.95.19.11211.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Fatrai S, Elghazi L, Balcazar N, Cras-Méneur C, Krits I, Kiyokawa H, et al. Akt induces β-cell proliferation by regulating cyclin D1, cyclin D2, and p21 levels and cyclin-dependent kinase-4 activity. Diabetes. 2006;55(2):318–25. https://doi.org/10.2337/diabetes.55.02.06.db05-0757%JDiabetes.

    Article  PubMed  CAS  Google Scholar 

  32. Shaw M, Cohen P, Alessi DR. Further evidence that the inhibition of glycogen synthase kinase-3beta by IGF-1 is mediated by PDK1/PKB-induced phosphorylation of Ser-9 and not by dephosphorylation of Tyr-216. FEBS Lett. 1997;416(3):307–11. https://doi.org/10.1016/s0014-5793(97)01235-0.

    Article  PubMed  CAS  Google Scholar 

  33. Lu X, Pang Y, Cao H, Liu X, Tu L, Shen Y, et al. Integrated screens identify CDK1 as a therapeutic target in advanced gastrointestinal stromal tumors. Can Res. 2021;81(9):2481–94. https://doi.org/10.1158/0008-5472.Can-20-3580.

    Article  CAS  Google Scholar 

  34. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci USA. 2008;105(52):20852–7. https://doi.org/10.1073/pnas.0810958105.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Zhang H, Qin G, Zhang C, Yang H, Liu J, Hu H, et al. TRAIL promotes epithelial-to-mesenchymal transition by inducing PD-L1 expression in esophageal squamous cell carcinomas. J Exp Clin Cancer Res. 2021;40(1):209. https://doi.org/10.1186/s13046-021-01972-0.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Tran H, Bustos D, Yeh R, Rubinfeld B, Lam C, Shriver S, et al. HectD1 E3 ligase modifies adenomatous polyposis coli (APC) with polyubiquitin to promote the APC-axin interaction. J Biol Chem. 2013;288(6):3753–67. https://doi.org/10.1074/jbc.M112.415240.

    Article  PubMed  CAS  Google Scholar 

  37. Oikonomaki M, Bady P, Hegi ME. Ubiquitin specific peptidase 15 (USP15) suppresses glioblastoma cell growth via stabilization of HECTD1 E3 ligase attenuating WNT pathway activity. Oncotarget. 2017;8(66):110490–502. https://doi.org/10.18632/oncotarget.22798.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was funded by the Beijing Medical Award Foundation (No. YXJL-2022-0080-0184).

Funding

This research was funded by the Beijing Medical Award Foundation (No. YXJL-2022–0080-0184).

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Authors and Affiliations

  1. Department of Thoracic Surgery, Esophagus and Mediastinum, Harbin Medical University Cancer Hospital, 150# Haping Road, Harbin, Heilongjiang, China

    Jinfeng Zhang, Yanzhong Xin, Xiaodong Ling, Hao Liang, Luquan Zhang, Chengyuan Fang & Jianqun Ma

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Zhang, J., Xin, Y., Ling, X. et al. Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression. Human Cell 37, 245–257 (2024). https://doi.org/10.1007/s13577-023-01005-2

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