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:

Heat-shock protein 90α protects NME1 against degradation and suppresses metastasis of breast cancer

British Journal of Cancer volume 129, pages 1679–1691 (2023)Cite this article

Subjects

Abstract

Background

NME1 has been exploited as a potential translational target for decades. Substantial efforts have been made to upregulate the expression of NME1 and restore its anti-metastasis function in metastatic cancer.

Methods

Cycloheximide (CHX) chase assay was used to measure the steady-state protein stability of NME1 and HSP90α. The NME1-associating proteins were identified by immunoprecipitation combined with mass spectrometric analysis. Gene knockdown and overexpression were employed to examine the impact of HSP90AA1 on intracellular NME1 degradation. The motility and invasiveness of breast cancer cells were examined in vitro using wound healing and transwell invasion assays. The orthotopic spontaneous metastasis and intra-venous experimental metastasis assays were used to test the formation of metastasis in vivo, respectively.

Results

HSP90α interacts with NME1 and increases NME1 lifetime by impeding its ubiquitin-proteasome-mediated degradation. HSP90α overexpression significantly inhibits the metastatic potential of breast cancer cells in vitro and in vivo. A novel cell-permeable peptide, OPT22 successfully mimics the HSP90α function and prolongs the life span of endogenous NME1, resulting in reduced metastasis of breast cancer.

Conclusion

These results not only reveal a new mechanism of NME1 degradation but also pave the way for the development of new and effective approaches to metastatic cancer therapy.

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: Protein degradation is an important means to regulate NME1 abundance.
Fig. 2: HSP90α is positively correlated with the intracellular stability of NME1.
Fig. 3: SUMOylation regulates NME1 lifetime through HSP90α.
Fig. 4: HSP90AA1 overexpression inhibits the metastatic potential of breast cancer cells.
Fig. 5: Expression of NME1-binding domain of HSP90α improves the lifetime of NME1.
Fig. 6: Peptide OPT22 functionally imitates HSP90α to promote NME1 stability.

Similar content being viewed by others

Data availability

All data generated or analysed in this study that are relevant to the results presented in this article are included in this article and its supplementary information files (Additional files). Other data that were not relevant to the results presented here are available from the corresponding author upon reasonable request.

References

  1. Yoshida BA, Sokoloff MM, Welch DR, Rinker-Schaeffer CW. Metastasis-suppressor genes: a review and perspective on an emerging field. J Natl Cancer Inst. 2000;92:1717–30.

    Article  CAS  PubMed  Google Scholar 

  2. Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, et al. Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst. 1988;80:200–4.

    Article  CAS  PubMed  Google Scholar 

  3. Yu L, Wang X, Zhang W, Khan E, Lin C, Guo C. The multiple regulation of metastasis suppressor NM23-H1 in cancer. Life Sci. 2021;268:118995.

    Article  CAS  PubMed  Google Scholar 

  4. Kuo KT, Chen CL, Chou TY, Yeh CT, Lee WH, Wang LS. Nm23H1 mediates tumor invasion in esophageal squamous cell carcinoma by regulation of CLDN1 through the AKT signaling. Oncogenesis 2016;5:e239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Li MQ, Shao J, Meng YH, Mei J, Wang Y, Li H, et al. NME1 suppression promotes growth, adhesion and implantation of endometrial stromal cells via Akt and MAPK/Erk1/2 signal pathways in the endometriotic milieu. Hum Reprod. 2013;28:2822–31.

    Article  CAS  PubMed  Google Scholar 

  6. Marshall JC, Collins J, Marino N, Steeg P. The Nm23-H1 metastasis suppressor as a translational target. Eur J Cancer. 2010;46:1278–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ouatas T, Halverson D, Steeg PS. Dexamethasone and medroxyprogesterone acetate elevate Nm23-H1 metastasis suppressor gene expression in metastatic human breast carcinoma cells: new uses for old compounds. Clin Cancer Res. 2003;9:3763–72.

    CAS  PubMed  Google Scholar 

  8. Lim J, Jang G, Kang S, Lee G, Nga do TT, Phuong, et al. Cell-permeable NM23 blocks the maintenance and progression of established pulmonary metastasis. Cancer Res. 2011;71:7216–25.

    Article  CAS  PubMed  Google Scholar 

  9. Chen W, Xiong S, Li J, Li X, Liu Y, Zou C, et al. The ubiquitin E3 ligase SCF-FBXO24 recognizes deacetylated nucleoside diphosphate kinase A to enhance its degradation. Mol Cell Biol. 2015;35:1001–13.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fiore LS, Ganguly SS, Sledziona J, Cibull ML, Wang C, Richards DL, et al. c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer. Oncogene. 2014;33:4508–20.

    Article  CAS  PubMed  Google Scholar 

  11. Khera L, Paul C, Kaul R. Hepatitis C Virus E1 protein promotes cell migration and invasion by modulating cellular metastasis suppressor Nm23-H1. Virology. 2017;506:110–20.

    Article  CAS  PubMed  Google Scholar 

  12. Paul C, Khera L, Kaul R. Hepatitis C virus core protein interacts with cellular metastasis suppressor Nm23-H1 and promotes cell migration and invasion. Arch Virol. 2019;164:1271–85.

    Article  CAS  PubMed  Google Scholar 

  13. Holliday DL, Speirs V. Choosing the right cell line for breast cancer research. Breast Cancer Res. 2011;13:215.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Dai X, Cheng H, Bai Z, Li J. Breast cancer cell line classification and its relevance with breast tumor subtyping. J Cancer. 2017;8:3131–41.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Singh B, Tai K, Madan S, Raythatha MR, Cady AM, Braunlin M, et al. Selection of metastatic breast cancer cells based on adaptability of their metabolic state. PLoS ONE. 2012;7:e36510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hartsough MT, Clare SE, Mair M, Elkahloun AG, Sgroi D, Osborne CK, et al. Elevation of breast carcinoma Nm23-H1 metastasis suppressor gene expression and reduced motility by DNA methylation inhibition. Cancer Res. 2001;61:2320–7.

    CAS  PubMed  Google Scholar 

  17. Yu BYK, Tossounian MA, Hristov SD, Lawrence R, Arora P, Tsuchiya Y, et al. Regulation of metastasis suppressor NME1 by a key metabolic cofactor coenzyme A. Redox Biol. 2021;44:101978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schopf FH, Biebl MM, Buchner J. The HSP90 chaperone machinery. Nat Rev Mol Cell Biol. 2017;18:345–60.

    Article  CAS  PubMed  Google Scholar 

  19. Ciechanover A, Schwartz AL. The ubiquitin-proteasome pathway: the complexity and myriad functions of proteins death. Proc Natl Acad Sci USA. 1998;95:2727–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Salerno M, Palmieri D, Bouadis A, Halverson D, Steeg PS. Nm23-H1 metastasis suppressor expression level influences the binding properties, stability, and function of the kinase suppressor of Ras1 (KSR1) Erk scaffold in breast carcinoma cells. Mol Cell Biol. 2005;25:1379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hua K, Feng W, Cao Q, Zhou X, Lu X, Feng Y. Estrogen and progestin regulate metastasis through the PI3K/AKT pathway in human ovarian cancer. Int J Oncol. 2008;33:959–67.

    CAS  PubMed  Google Scholar 

  22. Zhang X, Fu LJ, Liu XQ, Hu ZY, Jiang Y, Gao RF, et al. nm23 regulates decidualization through the PI3K-Akt-mTOR signaling pathways in mice and humans. Hum Reprod. 2016;31:2339–51.

    Article  CAS  PubMed  Google Scholar 

  23. Abu-Taha IH, Vettel C, Wieland T. Targeting altered Nme heterooligomerization in disease? Oncotarget. 2018;9:1492–3.

    Article  PubMed  Google Scholar 

  24. Chen Y, Qian C, Guo C, Ge F, Zhang X, Gao X, et al. A Cys/Ser mutation of NDPK-A stabilizes its oligomerization state and enhances its activity. J Biochem. 2010;148:149–55.

    Article  CAS  PubMed  Google Scholar 

  25. Kim YI, Park S, Jeoung DI, Lee H. Point mutations affecting the oligomeric structure of Nm23-H1 abrogates its inhibitory activity on colonization and invasion of prostate cancer cells. Biochem Biophys Res. Commun. 2003;307:281–9.

    Article  CAS  PubMed  Google Scholar 

  26. Postel EH. NM23-NDP kinase. Int J Biochem Cell Biol. 1998;30:1291–5.

    Article  CAS  PubMed  Google Scholar 

  27. Souza TA, Trindade DM, Tonoli CC, Santos CR, Ward RJ, Arni RK, et al. Molecular adaptability of nucleoside diphosphate kinase b from trypanosomatid parasites: stability, oligomerization and structural determinants of nucleotide binding. Mol Biosyst. 2011;7:2189–95.

    Article  CAS  PubMed  Google Scholar 

  28. Webb PA, Perisic O, Mendola CE, Backer JM, Williams RL. The crystal structure of a human nucleoside diphosphate kinase, NM23-H2. J Mol Biol. 1995;251:574–87.

    Article  CAS  PubMed  Google Scholar 

  29. Li YJ, Liu W, Saini V, Wong YH. Mutations at the dimer interface and surface residues of Nm23-H1 metastasis suppressor affect its expression and function. Mol Cell Biochem. 2020;474:95–112.

    Article  CAS  PubMed  Google Scholar 

  30. Wayne N, Mishra P, Bolon DN. Hsp90 and client protein maturation. Methods Mol Biol. 2011;787:33–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Echeverria PC, Bernthaler A, Dupuis P, Mayer B, Picard D. An interaction network predicted from public data as a discovery tool: application to the Hsp90 molecular chaperone machine. PLoS ONE. 2011;6:e26044.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li ZN, Luo Y. HSP90 inhibitors and cancer: prospects for use in targeted therapies (Review). Oncol Rep. 2023;49:6.

  33. Hahn JS. The Hsp90 chaperone machinery: from structure to drug development. BMB Rep. 2009;42:623–30.

    Article  CAS  PubMed  Google Scholar 

  34. Giese A, Loo MA, Tran N, Haskett D, Coons SW, Berens ME. Dichotomy of astrocytoma migration and proliferation. Int J Cancer. 1996;67:275–82.

    Article  CAS  PubMed  Google Scholar 

  35. Hatzikirou H, Basanta D, Simon M, Schaller K, Deutsch A. ‘Go or grow’: the key to the emergence of invasion in tumour progression? Math Med Biol. 2012;29:49–65.

    Article  CAS  PubMed  Google Scholar 

  36. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527:472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature. 2015;527:525–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Otvos L Jr, Wade JD. Current challenges in peptide-based drug discovery. Front Chem. 2014;2:62.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China grants (32370627, 82360605, 81773028).

Author information

Author notes

  1. These authors contributed equally: Yanchao Zhang, Guomeng Zhao.

Authors and Affiliations

  1. Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, People’s Republic of China

    Yanchao Zhang, Jinyao Li & Changying Guo

  2. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, People’s Republic of China

    Yanchao Zhang

  3. Institute of Modern Biology, Nanjing University, Nanjing, People’s Republic of China

    Guomeng Zhao

  4. Department of Protein and Antibody Engineering, School of Pharmacy, Binzhou Medical University, Yantai, People’s Republic of China

    Liting Yu

  5. School of Life Science and Technology, China Pharmaceutical University, Nanjing, People’s Republic of China

    Xindong Wang, Yao Meng & Jinlei Mao

  6. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing People’s Hospital, Nanjing, People’s Republic of China

    Ziyi Fu & Yongmei Yin

  7. Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Xun Wang

Authors
  1. Yanchao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guomeng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liting Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xindong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yao Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinlei Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ziyi Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yongmei Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jinyao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Changying Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YCZ and GMZ were responsible for designing the work, acquiring data and interpreting main results. LTY, XDW, YM and JLM validated some results and performed bioinformatic analysis. ZYF and YMY collected tumour samples from cancer patients and performed IHC analysis. JYL and XW managed the programme and drug efficacy evaluation. CYG was responsible for supervision, funding acquisition and manuscript preparation.

Corresponding authors

Correspondence to Yongmei Yin, Jinyao Li, Xun Wang or Changying Guo.

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 (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

Zhang, Y., Zhao, G., Yu, L. et al. Heat-shock protein 90α protects NME1 against degradation and suppresses metastasis of breast cancer. Br J Cancer 129, 1679–1691 (2023). https://doi.org/10.1038/s41416-023-02435-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-023-02435-3

Search

Advanced search

Quick links