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Downregulated circPOKE promotes breast cancer metastasis through activation of the USP10-Snail axis

Oncogene volume 42, pages 3236–3251 (2023)Cite this article

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Abstract

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among females. Metastasis accounts for the majority of BC related deaths. One feasible strategy to solve this challenging problem is to disrupt the capabilities required for tumor metastasis. Herein, we verified a novel metastasis suppressive circRNA, circPOKE in BC. circPOKE was downregulated in primary and metastatic BC tissues and overexpression of circPOKE inhibited the metastatic potential but not the proliferative ability of BC cells in vitro and in vivo. Mechanistically, circPOKE competitively binds to USP10, and reduces its binding to Snail, a key transcriptional regulator of EMT, thereby inhibiting Snail stability via the protein-ubiquitination degradation pathway. In addition, we found that circPOKE could be secreted into the extracellular space via exosomes and that exosome-carried circPOKE significantly inhibited the invasive capabilities of BC cells in vitro and in vivo. Furthermore, the levels of circPOKE, USP10 and Snail are clinically relevant in BC, suggesting that circPOKE may be used as a potential therapeutic target for patients with BC metastasis.

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Fig. 1: circPOKE is downregulated in BC.
Fig. 2: Overexpression circPOKE inhibit BC migration and invasion but not growth.
Fig. 3: circPOKE inhibit BC metastases through interacting with USP10.
Fig. 4: circPOKE promotes ubiquitin modification of Snail by competitive binding USP10.
Fig. 5: Overexpression circPOKE inhibits the stemness of BC cells.
Fig. 6: Overexpression of Snail partially reverses BC cell phenotype induced by circPOKE.
Fig. 7: Exo-circPOKE inhibits tumor metastasis in vivo.
Fig. 8: Clinical relevance of circPOKE, USP10 and Snail in patients with BC.

Data availability

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

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Acknowledgements

We thank Prof. Hailin Tang of the Sun Yat-sen University Cancer Center for offering clinical BC specimens with associated anonymous information. Some of the clipart icons appearing in Figs. 1A, 7C and 8K were created with BioRender (https://biorender.com).

Funding

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 82103171, Jianbo Feng) and the Natural Science Foundation of Hunan Province (No. 2021JJ30612, Jianbo Feng; 2020JJ4551, Xuyu Zu), and the Clinical Medical Research “4310” Program of the University of South China (20224310NHYCG07).

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  1. Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, PR China

    Yan Luo, Qingyun Zhu, Shasha Xiang, Qi Wang, Jun Li, Xiguang Chen, Wen Yan, Jianbo Feng & Xuyu Zu

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Contributions

X.Z. and J.F. conceived of the study and carried out its design. X.Z., J.F. and Y.L. wrote, reviewed and revised the manuscript; Y.L., Q.Z., S.X., Q.W. performed the experiments; J.L., X.C. and W.Y. analyzed and interpreted the data; J.F. provided constructive feedback and guidance; X.Z. completed critical revisions and proofread the manuscript. All authors reviewed the manuscript and approved the final manuscript.

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Correspondence to Jianbo Feng or Xuyu Zu.

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The Animal Ethics Committee of the University of South China approved all animal experiments (permission No. USC202010XS11). All participants gave informed consent to be included in the study.

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Luo, Y., Zhu, Q., Xiang, S. et al. Downregulated circPOKE promotes breast cancer metastasis through activation of the USP10-Snail axis. Oncogene 42, 3236–3251 (2023). https://doi.org/10.1038/s41388-023-02823-2

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