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.
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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.
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Acknowledgements
This work was supported by National Natural Science Foundation of China grants (32370627, 82360605, 81773028).
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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.
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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
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DOI: https://doi.org/10.1038/s41416-023-02435-3