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.

  • Article
  • Published:

UCHL3 promotes ovarian cancer progression by stabilizing TRAF2 to activate the NF-κB pathway

Oncogene volume 39, pages 322–333 (2020)Cite this article

Subjects

Abstract

The inflammatory response plays an important role in carcinogenesis. However, the functional role and mechanism of the UCHL3-associated inflammatory response in ovarian cancer remain to be characterized. Here, we report that increased expression of UCHL3 facilitates tumourigenesis by targeting TRAF2 protein, thereby enhancing the inflammatory response. The expression of UCHL3 is elevated in ovarian cancer patients and is associated with an unfavourable prognosis. Genetic ablation of UCHL3 was found to markedly block ovarian cancer cell proliferation, viability and migration both in vitro and in vivo. Mechanistically, luciferase pathway screening results show that NF-κB signalling is clearly activated compared with other pathways. UCHL3 was found to activate NF-κB signalling by deubiquitinating and stabilizing TRAF2, leading to tumourigenesis. Our results indicate that highly expressed UCHL3 enhances inflammation by stabilizing TRAF2, which in turn facilitates tumourigenesis in ovarian cancer, and that UCHL3 is a potential target for ovarian cancer patients with increased inflammation.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Gupta KK, Gupta VK, Naumann RW. Ovarian cancer: screening and future directions. Int J Gynecol Cancer. 2019;29:195–200.

    PubMed  Google Scholar 

  2. Menon U, Griffin M, Gentry-Maharaj A. Ovarian cancer screening—current status, future directions. Gynecol Oncol. 2014;132:490–5.

    PubMed  PubMed Central  Google Scholar 

  3. Moufarrij S, Dandapani M, Arthofer E, Gomez S, Srivastava A, Lopez-Acevedo M, et al. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics. 2019;11:7.

    PubMed  PubMed Central  Google Scholar 

  4. Kisielewski R, Tolwinska A, Mazurek A, Laudanski P. Inflammation and ovarian cancer—current views. Ginekol Pol.2013;84:293–7.

    PubMed  Google Scholar 

  5. Maccio A, Madeddu C. Inflammation and ovarian cancer. Cytokine. 2012;58:133–47.

    CAS  PubMed  Google Scholar 

  6. White KL, Schildkraut JM, Palmieri RT, Iversen ES Jr., Berchuck A, Vierkant RA, et al. Ovarian cancer risk associated with inherited inflammation-related variants. Cancer Res. 2012;72:1064–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Browning L, Patel MR, Horvath EB, Tawara K, Jorcyk CL. IL-6 and ovarian cancer: inflammatory cytokines in promotion of metastasis. Cancer Manag Res. 2018;10:6685–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Cheong KM. Pelvic inflammatory disease and ovarian cancer. Lancet Oncol. 2011;12:1183–4. author reply1184-1185

    PubMed  Google Scholar 

  9. Gupta M, Babic A, Beck AH, Terry K. TNF-alpha expression, risk factors, and inflammatory exposures in ovarian cancer: evidence for an inflammatory pathway of ovarian carcinogenesis? Hum Pathol. 2016;54:82–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Li S, Wang D, Zhao J, Weathington NM, Shang D, Zhao Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E-cadherin-mediated adherens junctions. FASEB J. 2018;32:230–42.

    CAS  PubMed  Google Scholar 

  11. Frickel EM, Quesada V, Muething L, Gubbels MJ, Spooner E, Ploegh H, et al. Apicomplexan UCHL3 retains dual specificity for ubiquitin and Nedd8 throughout evolution. Cell Microbiol. 2007;9:1601–10.

    CAS  PubMed  Google Scholar 

  12. Artavanis-Tsakonas K, Weihofen WA, Antos JM, Coleman BI, Comeaux CA, Duraisingh MT, et al. Characterization and structural studies of the Plasmodium falciparum ubiquitin and Nedd8 hydrolase UCHL3. J Biol Chem. 2010;285:6857–66.

    CAS  PubMed  Google Scholar 

  13. Kim JY, Lee JM, Cho JY. Ubiquitin C-terminal hydrolase-L3 regulates Smad1 ubiquitination and osteoblast differentiation. FEBS Lett. 2011;585:1121–6.

    CAS  PubMed  Google Scholar 

  14. Setsuie R, Suzuki M, Tsuchiya Y, Wada K. Skeletal muscles of Uchl3 knockout mice show polyubiquitinated protein accumulation and stress responses. Neurochem Int. 2010;56:911–8.

    CAS  PubMed  Google Scholar 

  15. Wood MA, Kaplan MP, Brensinger CM, Guo W, Abel T. Ubiquitin C-terminal hydrolase L3 (Uchl3) is involved in working memory. Hippocampus. 2005;15:610–21.

    CAS  PubMed  Google Scholar 

  16. Mtango NR, Sutovsky M, Susor A, Zhong Z, Latham KE, Sutovsky P. Essential role of maternal UCHL1 and UCHL3 in fertilization and preimplantation embryo development. J Cell Physiol. 2012;227:1592–603.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Suzuki M, Setsuie R, Wada K. Ubiquitin carboxyl-terminal hydrolase l3 promotes insulin signaling and adipogenesis. Endocrinology. 2009;150:5230–9.

    CAS  PubMed  Google Scholar 

  18. Zhao P, Guo T, Qian L, Wang X, Yuan Y, Cheng Q, et al. Ubiquitin C-terminal hydrolase-L3 promotes interferon antiviral activity by stabilizing type I-interferon receptor. Antivir Res. 2017;144:120–9.

    CAS  PubMed  Google Scholar 

  19. Mtango NR, Sutovsky M, Vandevoort CA, Latham KE, Sutovsky P. Essential role of ubiquitin C-terminal hydrolases UCHL1 and UCHL3 in mammalian oocyte maturation. J Cell Physiol. 2012;227:2022–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nishi R, Wijnhoven PWG, Kimura Y, Matsui M, Konietzny R, Wu Q, et al. The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage. Sci Rep. 2018;8:17891.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Sano Y, Furuta A, Setsuie R, Kikuchi H, Wang YL, Sakurai M, et al. Photoreceptor cell apoptosis in the retinal degeneration of Uchl3-deficient mice. Am J Pathol. 2006;169:132–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Song HM, Lee JE, Kim JH. Ubiquitin C-terminal hydrolase-L3 regulates EMT process and cancer metastasis in prostate cell lines. Biochem Biophys Res Commun. 2014;452:722–7.

    CAS  PubMed  Google Scholar 

  23. Popp MW, Artavanis-Tsakonas K, Ploegh HL. Substrate filtering by the active site crossover loop in UCHL3 revealed by sortagging and gain-of-function mutations. J Biol Chem. 2009;284:3593–602.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wada H, Kito K, Caskey LS, Yeh ET, Kamitani T. Cleavage of the C-terminus of NEDD8 by UCH-L3. Biochem Biophys Res Commun. 1998;251:688–92.

    CAS  PubMed  Google Scholar 

  25. Fang Y, Fu D, Shen XZ. The potential role of ubiquitin c-terminal hydrolases in oncogenesis. Biochim Biophys Acta. 2010;1806:1–6.

    CAS  PubMed  Google Scholar 

  26. Zhang Y, Zhou L, Rouge L, Phillips AH, Lam C, Liu P, et al. Conformational stabilization of ubiquitin yields potent and selective inhibitors of USP7. Nat Chem Biol. 2013;9:51–58.

    CAS  PubMed  Google Scholar 

  27. Omori E, Matsumoto K, Sanjo H, Sato S, Akira S, Smart RC, et al. TAK1 is a master regulator of epidermal homeostasis involving skin inflammation and apoptosis. J Biol Chem. 2006;281:19610–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Etemadi N, Chopin M, Anderton H, Tanzer MC, Rickard JA, Abeysekera W, et al. TRAF2 regulates TNF and NF-kappaB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife. 2015;4:10592.

  29. Riedlinger T, Dommerholt MB, Wijshake T, Kruit JK, Huijkman N, Dekker D, et al. NF-kappaB p65 serine 467 phosphorylation sensitizes mice to weight gain and TNFalpha-or diet-induced inflammation. Biochim Biophys Acta Mol Cell Res. 2017;1864:1785–98.

    CAS  PubMed  Google Scholar 

  30. Reyes-Turcu FE, Ventii KH, Wilkinson KD. Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem. 2009;78:363–97.

    CAS  PubMed  Google Scholar 

  31. Borghi A, Verstrepen L, Beyaert R. TRAF2 multitasking in TNF receptor-induced signaling to NF-kappaB, MAP kinases and cell death. Biochem Pharmacol. 2016;116:1–10.

    CAS  PubMed  Google Scholar 

  32. Peramuhendige P, Marino S, Bishop RT, de Ridder D, Khogeer A, Baldini I, et al. TRAF2 in osteotropic breast cancer cells enhances skeletal tumour growth and promotes osteolysis. Sci Rep. 2018;8:39.

    PubMed  PubMed Central  Google Scholar 

  33. Zhao J, Li H, Min L, Han X, Shu P, Yang Y, et al. High expression of tumor necrosis factor receptor-associated factor 2 promotes tumor metastasis and is associated with unfavorable prognosis in gastric cancer. J Gastroenterol Hepatol. 2018;33:431–42.

    CAS  PubMed  Google Scholar 

  34. Zhang J, Dai WJ, Yang XZ. Methylation status of TRAF2 is associated with the diagnosis and prognosis of gastric cancer. Int J Clin Exp Pathol. 2015;8:14228–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wei B, Ruan J, Mi Y, Hu J, Zhang J, Wang Z, et al. Knockdown of TNF receptor-associated factor 2 (TRAF2) modulates in vitro growth of TRAIL-treated prostate cancer cells. Biomed Pharmacol. 2017;93:462–9.

    CAS  Google Scholar 

  36. Wei B, Liang J, Hu J, Mi Y, Ruan J, Zhang J, et al. TRAF2 is a valuable prognostic biomarker in patients with prostate cancer. Med Sci Monit. 2017;23:4192–204.

    PubMed  PubMed Central  Google Scholar 

  37. Li L, Soetandyo N, Wang Q, Ye Y. The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation. Biochim Biophys Acta. 2009;1793:346–53.

    CAS  PubMed  Google Scholar 

  38. Lin TB, Hsieh MC, Lai CY, Cheng JK, Chau YP, Ruan T, et al. Fbxo3-dependent Fbxl2 ubiquitination mediates neuropathic allodynia through the TRAF2/TNIK/GluR1 cascade. J Neurosci. 2015;35:16545–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Habelhah H, Frew IJ, Laine A, Janes PW, Relaix F, Sassoon D, et al. Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J. 2002;21:5756–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Wu CJ, Conze DB, Li X, Ying SX, Hanover JA, Ashwell JD. TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. EMBO J. 2005;24:1886–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Li X, Yang Y, Ashwell JD. TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2. Nature. 2002;416:345–7.

    PubMed  Google Scholar 

  42. Xiao N, Li H, Luo J, Wang R, Chen H, Chen J, et al. Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha-induced cancer cell migration. Biochem J. 2012;441:979–86.

    CAS  PubMed  Google Scholar 

  43. Zhong H, Wang D, Fang L, Zhang H, Luo R, Shang M, et al. Ubiquitin-specific proteases 25 negatively regulates virus-induced type I interferon signaling. PLoS ONE. 2013;8:e80976.

    PubMed  PubMed Central  Google Scholar 

  44. Tesio M, Tang Y, Mudder K, Saini M, von Paleske L, Macintyre E, et al. Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway. J Exp Med. 2015;212:525–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Trompouki E, Hatzivassiliou E, Tsichritzis T, Farmer H, Ashworth A, Mosialos G. CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature. 2003;424:793–6.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China [81602450] and the Fundamental Research Funds for the Central Universities [413000099] and Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund Project [cxpy2017005] and Foundation of Hunan Educational Committee (16B161).

Author information

Author notes

  1. These authors contributed equally: Ming-Hui Zhang, Hui-Hui Zhang

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Ming-Hui Zhang, Hui-Rong Shi & Shang-Ze Li

  2. College of Medicine, Hunan Normal University, Changsha, 410013, Hunan, China

    Hui-Hui Zhang

  3. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China

    Xue-Hua Du, Jie Gao & Chao Li

  4. Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, China

    Shang-Ze Li

Authors
  1. Ming-Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hui-Hui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue-Hua Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jie Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui-Rong Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shang-Ze Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shang-Ze Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, MH., Zhang, HH., Du, XH. et al. UCHL3 promotes ovarian cancer progression by stabilizing TRAF2 to activate the NF-κB pathway. Oncogene 39, 322–333 (2020). https://doi.org/10.1038/s41388-019-0987-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0987-z

This article is cited by

Search

Advanced search

Quick links