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:

Ubiquitin-specific protease 5 promotes bladder cancer progression through stabilizing Twist1

Oncogene volume 43, pages 703–713 (2024)Cite this article

Subjects

Abstract

Aberrant activation of the epithelial-mesenchymal transition (EMT) pathway drives the development of solid tumors, which is precisely regulated by core EMT-related transcription factors, including Twist1. However, the expression pattern and regulatory mechanism of Twist1 in the progression of bladder cancer is still unclear. In this study, we explore the role of Twist1 in the progression of bladder cancer. We discovered that the EMT regulon Twist1 protein, but not Twist1 mRNA, is overexpressed in bladder cancer samples using RT-qPCR, western blot and immunohistochemistry (IHC). Mechanistically, co-immunoprecipitation (Co-IP) coupled with liquid chromatography and tandem mass spectrometry identified USP5 as a binding partner of Twist1, and the binding of Twist1 to ubiquitin-specific protease 5 (USP5) stabilizes Twist through its deubiquitinase activity to activate the EMT. Further studies found that USP5 depletion reduces cell proliferation, invasion and the EMT in bladder cancer cells, and ectopic expression of Twist1 rescues the adverse effects of USP5 loss on cell invasion and the EMT. A xenograft tumor model was used to reconfirmed the inhibitor effect of silencing USP5 expression on tumorigenesis in vivo. In addition, USP5 protein levels are significantly elevated and positively associated with Twist1 levels in clinical bladder cancer samples. Collectively, our study revealed that USP5-Twist1 axis is a novel regulatory mechanism driving bladder cancer progression and that approaches targeting USP5 may become a promising cancer treatment strategy.

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: The Twist1 protein but not mRNA is overexpressed in bladder cancer.
Fig. 2: Twist1 physically associates with USP5.
Fig. 3: USP5 maintains the stability of Twist1 through deubiquitination.
Fig. 4: USP5 acts as an oncogene and enhances cell proliferation, invasiveness and the EMT in bladder cancer.
Fig. 5: Twist1 restores the inhibition of cell invasion and EMT mediated by USP5 depletion.
Fig. 6: USP5 expression correlates with Twist1 protein levels and predicts poor outcomes for patients bladder cancer.

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Yin H, Zhang C, Gou X, He W, Gan D. Identification of a 13?mRNA signature for predicting disease progression and prognosis in patients with bladder cancer. Oncol Rep. 2020;43:379–94.

    CAS  PubMed  Google Scholar 

  3. Yin H, Zhang C, Wei Z, He W, Xu N, Xu Y, et al. EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation. Cell Death Dis. 2022;13:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brabletz S, Schuhwerk H, Brabletz T, Stemmler MP. Dynamic EMT: a multi-tool for tumor progression. EMBO J. 2021;40:e108647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.

    Article  CAS  PubMed  Google Scholar 

  6. Beck B, Lapouge G, Rorive S, Drogat B, Desaedelaere K, Delafaille S, et al. Different levels of Twist1 regulate skin tumor initiation, stemness, and progression. Cell Stem Cell. 2015;16:67–79.

    Article  CAS  PubMed  Google Scholar 

  7. Eckert MA, Lwin TM, Chang AT, Kim J, Danis E, Ohno-Machado L, et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011;19:372–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhao Z, Rahman MA, Chen ZG, Shin DM. Multiple biological functions of Twist1 in various cancers. Oncotarget. 2017;8:20380–93.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Han S, Wang R, Zhang Y, Li X, Gan Y, Gao F, et al. The role of ubiquitination and deubiquitination in tumor invasion and metastasis. Int J Biol Sci. 2022;18:2292–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhou A, Lin K, Zhang S, Ma L, Xue J, Morris SA, et al. Gli1-induced deubiquitinase USP48 aids glioblastoma tumorigenesis by stabilizing Gli1. EMBO Rep. 2017;18:1318–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai X, Feng S, Zhang J, Qiu W, Qian M, Wang Y. USP18 deubiquitinates and stabilizes Twist1 to promote epithelial-mesenchymal transition in glioblastoma cells. Am J Cancer Res. 2020;10:1156–69.

    PubMed  PubMed Central  Google Scholar 

  12. He J, Lee HJ, Saha S, Ruan D, Guo H, Chan CH. Inhibition of USP2 eliminates cancer stem cells and enhances TNBC responsiveness to chemotherapy. Cell Death Dis. 2019;10:285.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lin J, Zhang W, Niu LT, Zhu YM, Weng XQ, Sheng Y, et al. TRIB3 stabilizes high TWIST1 expression to promote rapid APL progression and ATRA resistance. Clin Cancer Res. 2019;25:6228–42.

    Article  CAS  PubMed  Google Scholar 

  14. Meng J, Ai X, Lei Y, Zhong W, Qian B, Qiao K, et al. USP5 promotes epithelial-mesenchymal transition by stabilizing SLUG in hepatocellular carcinoma. Theranostics. 2019;9:573–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lambies G, García de Herreros A, Díaz VM. The role of DUBs in the post-translational control of cell migration. Essays Biochem. 2019;63:579–94.

    Article  CAS  PubMed  Google Scholar 

  16. Pastushenko I, Blanpain C. EMT transition states during tumor progression and metastasis. Trends Cell Biol. 2019;29:212–26.

    Article  CAS  PubMed  Google Scholar 

  17. Iyengar PV, Marvin DL, Lama D, Tan TZ, Suriyamurthy S, Xie F, et al. TRAF4 inhibits bladder cancer progression by promoting BMP/SMAD signaling. Mol Cancer Res. 2022;20:1516–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alexander NR, Tran NL, Rekapally H, Summers CE, Glackin C, Heimark RL. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 2006;66:3365–9.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Z, Xie D, Li X, Wong YC, Xin D, Guan XY, et al. Significance of TWIST expression and its association with E-cadherin in bladder cancer. Hum Pathol. 2007;38:598–606.

    Article  CAS  PubMed  Google Scholar 

  20. Fondrevelle ME, Kantelip B, Reiter RE, Chopin DK, Thiery JP, Monnien F, et al. The expression of Twist has an impact on survival in human bladder cancer and is influenced by the smoking status. Urol Oncol. 2009;27:268–76.

    Article  CAS  PubMed  Google Scholar 

  21. Dai C, Liu Y, Yang R, Zhou L. Clinical significance of MACC1, Twist1, and KAI1 expressions in infiltrating urothelial carcinoma of the bladder. Int J Clin Exp Pathol. 2019;12:3877–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tang X, Xing J, Li W, Wu Z, Zhang K, Zheng J. Expression of transcription factor Twist1 in bladder urothelial carcinoma and its clinical significance. J BUON. 2013;18:211–9.

    PubMed  Google Scholar 

  23. Ning F, Xin H, Liu J, Lv C, Xu X, Wang M, et al. Structure and function of USP5: Insight into physiological and pathophysiological roles. Pharmacol Res. 2020;157:104557.

    Article  CAS  PubMed  Google Scholar 

  24. Potu H, Peterson LF, Pal A, Verhaegen M, Cao J, Talpaz M, et al. Usp5 links suppression of p53 and FAS levels in melanoma to the BRAF pathway. Oncotarget. 2014;5:5559–69.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Li XY, Wu HY, Mao XF, Jiang LX, Wang YX. USP5 promotes tumorigenesis and progression of pancreatic cancer by stabilizing FoxM1 protein. Biochem Biophys Res Commun. 2017;492:48–54.

    Article  CAS  PubMed  Google Scholar 

  26. Wang S, Juan J, Zhang Z, Du Y, Xu Y, Tong J, et al. Inhibition of the deubiquitinase USP5 leads to c-Maf protein degradation and myeloma cell apoptosis. Cell Death Dis. 2017;8:e3058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ma X, Qi W, Pan H, Yang F, Deng J. Overexpression of USP5 contributes to tumorigenesis in non-small cell lung cancer via the stabilization of β-catenin protein. Am J Cancer Res. 2018;8:2284–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Pan J, Qiao Y, Chen C, Zang H, Zhang X, Qi F, et al. USP5 facilitates non-small cell lung cancer progression through stabilization of PD-L1. Cell Death Dis. 2021;12:1051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xue S, Wu W, Wang Z, Lu G, Sun J, Jin X, et al. USP5 promotes metastasis in non-small cell lung cancer by inducing epithelial-mesenchymal transition via Wnt/β-Catenin pathway. Front Pharmacol. 2020;11:668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dyrskjøt L, Kruhøffer M, Thykjaer T, Marcussen N, Jensen JL, Møller K, et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 2004;64:4040–8.

    Article  PubMed  Google Scholar 

  31. Lee JS, Leem SH, Lee SY, Kim SC, Park ES, Kim SB, et al. Expression signature of E2F1 and its associated genes predict superficial to invasive progression of bladder tumors. J Clin Oncol. 2010;28:2660–7.

    Article  CAS  PubMed  Google Scholar 

  32. Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol. 2006;24:778–89.

    Article  CAS  PubMed  Google Scholar 

  33. Yin H, Yang X, Gu W, Liu Y, Li X, Huang X, et al. HMGB1-mediated autophagy attenuates gemcitabine-induced apoptosis in bladder cancer cells involving JNK and ERK activation. Oncotarget. 2017;8:71642–56.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Yin H, He W, Li Y, Xu N, Zhu X, Lin Y, et al. Loss of DUSP2 predicts a poor prognosis in patients with bladder cancer. Hum Pathol. 2019;85:152–61.

    Article  CAS  PubMed  Google Scholar 

  35. Cai H, Chen H, Huang Q, Zhu JM, Ke ZB, Lin YZ, et al. Ubiquitination-related molecular subtypes and a novel prognostic index for bladder cancer patients. Pathol Oncol Res. 2021;27:1609941.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by Natural Science Foundation of Fujian Province (No.2021J01715), Scientific Research Project of National Key Clinical Specialty Construction Project (No. 2022YBL-KF-05), and Class B Talent Research Project of the First Affiliated Hospital of Fujian Medical University (Grant number: YJCRC-B-XN2022).

Author information

Author notes

  1. These authors contributed equally: Hai Cai, Zhi-Bin Ke, Jia-Yin Chen, Xiao-Dong Li.

Authors and Affiliations

  1. Department of Urology, Urology Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Hai Cai, Zhi-Bin Ke, Jia-Yin Chen, Xiao-Dong Li, Jun-Ming Zhu, Yu-Ting Xue, Zhong-Tian Ruan, Zhen Wang, Fei Lin, Qing-Shui Zheng, Yong Wei, Xue-Yi Xue & Ning Xu

  2. Department of Urology, National Region Medical center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350212, China

    Hai Cai, Zhi-Bin Ke, Jia-Yin Chen, Xiao-Dong Li, Jun-Ming Zhu, Yu-Ting Xue, Zhong-Tian Ruan, Zhen Wang, Fei Lin, Qing-Shui Zheng, Yong Wei, Xue-Yi Xue & Ning Xu

  3. Fujian Key Laboratory of Precision Medicine for Cancer, the First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China

    Xue-Yi Xue & Ning Xu

Authors
  1. Hai Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhi-Bin Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia-Yin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao-Dong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jun-Ming Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yu-Ting Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhong-Tian Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qing-Shui Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yong Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xue-Yi Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ning Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CH, KZB, CJY, LXD conceived and designed the experiments and drafted the manuscript; ZJM, XYT, RZT, WZ participated in the design of the study and performed the statistical analysis; LF, ZQS participated in data curation; WY, XXY, XN conceived of the study. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xue-Yi Xue or Ning Xu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was approved by the Human Research Ethics Committee of Fujian Medical University, and the informed consent was obtained from patients. The animal study was approved by the Review Board of Animal Care and Use of Fujian Medical University.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, H., Ke, ZB., Chen, JY. et al. Ubiquitin-specific protease 5 promotes bladder cancer progression through stabilizing Twist1. Oncogene 43, 703–713 (2024). https://doi.org/10.1038/s41388-023-02936-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02936-8

Search

Advanced search

Quick links