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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.

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Data availability

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

References

  1. Giaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, et al. Breast Cancer Statistics, 2022. CA Cancer J Clin. 2022;72: 524–41.

  2. He X, Xu T, Hu W, Tan Y, Wang D, Wang Y, et al. Circular RNAs: Their Role in the Pathogenesis and Orchestration of Breast Cancer. Front Cell Dev Biol. 2021;9:647736.

    PubMed  PubMed Central  Google Scholar 

  3. Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, et al. Breast cancer metastasis: challenges and opportunities. Cancer Res. 2009;69:4951–3.

    CAS  PubMed  Google Scholar 

  4. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    PubMed  Google Scholar 

  5. Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: implications in development and cancer. Development. 2005;132:3151–61.

    CAS  PubMed  Google Scholar 

  6. Zhang Y, Zou X, Qian W, Weng X, Zhang L, Zhang L, et al. Enhanced PAPSS2/VCAN sulfation axis is essential for Snail-mediated breast cancer cell migration and metastasis. Cell Death Differ. 2019;26:565–79.

    CAS  PubMed  Google Scholar 

  7. Xie W, Jiang Q, Wu X, Wang L, Gao B, Sun Z, et al. IKBKE phosphorylates and stabilizes Snail to promote breast cancer invasion and metastasis. Cell Death Differ. 2022;29:1528–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y, Shi J, Chai K, Ying X, Zhou BP. The Role of Snail in EMT and Tumorigenesis. Curr Cancer Drug Targets. 2013;13:963–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kim NH, Song SH, Choi YH, Hwang KH, Yun JS, Song H, et al. Competing Endogenous RNA of Snail and Zeb1 UTR in Therapeutic Resistance of Colorectal Cancer. Int J Mol Sci. 2021;22:9589.

  10. Jin Y, Zhang Y, Li B, Zhang J, Dong Z, Hu X, et al. TRIM21 mediates ubiquitination of Snail and modulates epithelial to mesenchymal transition in breast cancer cells. Int J Biol Macromol. 2019;124:846–53.

    CAS  PubMed  Google Scholar 

  11. Jia Z, Wang M, Li S, Li X, Bai XY, Xu Z, et al. U-box ubiquitin ligase PPIL2 suppresses breast cancer invasion and metastasis by altering cell morphology and promoting SNAI1 ubiquitination and degradation. Cell Death Dis. 2018;9:63.

    PubMed  PubMed Central  Google Scholar 

  12. Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J. The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet. 2019;20:675–91.

    CAS  PubMed  Google Scholar 

  13. Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat Biotechnol. 2014;32:453–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhou WY, Cai ZR, Liu J, Wang DS, Ju HQ, Xu RH. Circular RNA: metabolism, functions and interactions with proteins. Mol Cancer. 2020;19:172.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Li X, Yang L, Chen LL. The Biogenesis, Functions, and Challenges of Circular RNAs. Mol Cell. 2018;71:428–42.

    CAS  PubMed  Google Scholar 

  16. Shang Q, Yang Z, Jia R, Ge S. The novel roles of circRNAs in human cancer. Mol Cancer. 2019;18:6.

    PubMed  PubMed Central  Google Scholar 

  17. Zeng Y, Du W, Huang Z, Wu S, Ou X, Zhang J, et al. Hsa_circ_0060467 promotes breast cancer liver metastasis by complexing with eIF4A3 and sponging miR-1205. Cell Death Discov. 2023;9:153.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu J, Jiang X, Zou A, Mai Z, Huang Z, Sun L, et al. circIGHG-Induced Epithelial-to-Mesenchymal Transition Promotes Oral Squamous Cell Carcinoma Progression via miR-142-5p/IGF2BP3 Signaling. Cancer Res. 2021;81:344–55.

    CAS  PubMed  Google Scholar 

  19. Liu P, Wang Z, Ou X, Wu P, Zhang Y, Wu S, et al. The FUS/circEZH2/KLF5/ feedback loop contributes to CXCR4-induced liver metastasis of breast cancer by enhancing epithelial-mesenchymal transition. Mol Cancer. 2022;21:198.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Li J, Li Z, Jiang P, Peng M, Zhang X, Chen K, et al. Circular RNA IARS (circ-IARS) secreted by pancreatic cancer cells and located within exosomes regulates endothelial monolayer permeability to promote tumor metastasis. J Exp Clin Cancer Res. 2018;37:177.

    PubMed  PubMed Central  Google Scholar 

  21. Zokaei E, Darbeheshti F, Rezaei N. Prospect of exosomal circular RNAs in breast Cancer: presents and future. Mol Biol Rep. 2022;49:6997–7011.

    CAS  PubMed  Google Scholar 

  22. Chen L, Zhong J, Liu JH, Liao DF, Shen YY, Zhong XL, et al. Pokemon Inhibits Transforming Growth Factor β-Smad4-Related Cell Proliferation Arrest in Breast Cancer through Specificity Protein 1. J Breast Cancer. 2019;22:15–28.

    PubMed  PubMed Central  Google Scholar 

  23. Zu X, Ma J, Liu H, Liu F, Tan C, Yu L, et al. Pro-oncogene Pokemon promotes breast cancer progression by upregulating survivin expression. Breast Cancer Res. 2011;13:R26.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Guarnerio J, Zhang Y, Cheloni G, Panella R, Mae Katon J, Simpson M, et al. Intragenic antagonistic roles of protein and circRNA in tumorigenesis. Cell Res. 2019;29:628–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Yuan Y, Zhang X, Du K, Zhu X, Chang S, Chen Y, et al. Circ_CEA promotes the interaction between the p53 and cyclin-dependent kinases 1 as a scaffold to inhibit the apoptosis of gastric cancer. Cell Death Dis. 2022;13:827.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lim R, Sugino T, Nolte H, Andrade J, Zimmermann B, Shi C, et al. Deubiquitinase USP10 regulates Notch signaling in the endothelium. Science. 2019;364:188–93.

    CAS  PubMed  Google Scholar 

  27. Unternaehrer JJ, Zhao R, Kim K, Cesana M, Powers JT, Ratanasirintrawoot S, et al. The epithelial-mesenchymal transition factor SNAIL paradoxically enhances reprogramming. Stem Cell Rep. 2014;3:691–8.

    CAS  Google Scholar 

  28. Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, et al. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells. Stem Cells. 2010;28:1435–45.

    CAS  PubMed  Google Scholar 

  29. Dong B and Wu Y. Epigenetic Regulation and Post-Translational Modifications of SNAI1 in Cancer Metastasis. Int J Mol Sci. 2021;22:11062

  30. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kumar S, Nandi A, Singh S, Regulapati R, Li N, Tobias JW, et al. Dll1(+) quiescent tumor stem cells drive chemoresistance in breast cancer through NF-κB survival pathway. Nat Commun. 2021;12:432.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Cooks T, Pateras IS, Jenkins LM, Patel KM, Robles AI, Morris J, et al. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat Commun. 2018;9:771.

    PubMed  PubMed Central  Google Scholar 

  33. Sun L, Xu R, Sun X, Duan Y, Han Y, Zhao Y, et al. Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell. Cytotherapy. 2016;18:413–22.

    CAS  PubMed  Google Scholar 

  34. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.

    CAS  PubMed  Google Scholar 

  35. Zhou SL, Zhou ZJ, Hu ZQ, Song CL, Luo YJ, Luo CB, et al. Genomic sequencing identifies WNK2 as a driver in hepatocellular carcinoma and a risk factor for early recurrence. J Hepatol. 2019;71:1152–63.

    CAS  PubMed  Google Scholar 

  36. Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147:275–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Schmidt JM, Panzilius E, Bartsch HS, Irmler M, Beckers J, Kari V, et al. Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation. Cell Rep. 2015;10:131–9.

    CAS  PubMed  Google Scholar 

  38. Jung HY, Fattet L, Tsai JH, Kajimoto T, Chang Q, Newton AC, et al. Apical-basal polarity inhibits epithelial-mesenchymal transition and tumour metastasis by PAR-complex-mediated SNAI1 degradation. Nat Cell Biol. 2019;21:359–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Moreno-Bueno G, Portillo F, Cano A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene. 2008;27:6958–69.

    CAS  PubMed  Google Scholar 

  40. Du WW, Yang W, Liu E, Yang Z, Dhaliwal P, Yang BB. Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2. Nucl Acids Res. 2016;44:2846–58.

    PubMed  PubMed Central  Google Scholar 

  41. Li J, Hu ZQ, Yu SY, Mao L, Zhou ZJ, Wang PC, et al. CircRPN2 Inhibits Aerobic Glycolysis and Metastasis in Hepatocellular Carcinoma. Cancer Res. 2022;82:1055–69.

    CAS  PubMed  Google Scholar 

  42. Senft D, Qi J, Ronai ZA. Ubiquitin ligases in oncogenic transformation and cancer therapy. Nat Rev Cancer. 2018;18:69–88.

    CAS  PubMed  Google Scholar 

  43. Xu J, Ji L, Liang Y, Wan Z, Zheng W, Song X, et al. CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther. 2020;5:298.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Li B, Zhu L, Lu C, Wang C, Wang H, Jin H, et al. circNDUFB2 inhibits non-small cell lung cancer progression via destabilizing IGF2BPs and activating anti-tumor immunity. Nat Commun. 2021;12:295.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol. 2002;3:155–66.

    CAS  PubMed  Google Scholar 

  46. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, et al. Dual regulation of Snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol. 2004;6:931–40.

    CAS  PubMed  Google Scholar 

  47. Liu T, Yu J, Deng M, Yin Y, Zhang H, Luo K, et al. CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat Commun. 2017;8:13923.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhu R, Liu Y, Zhou H, Li L, Li Y, Ding F, et al. Deubiquitinating enzyme PSMD14 promotes tumor metastasis through stabilizing SNAIL in human esophageal squamous cell carcinoma. Cancer Lett. 2018;418:125–34.

    CAS  PubMed  Google Scholar 

  49. Zhou H, Liu Y, Zhu R, Ding F, Cao X, Lin D, et al. OTUB1 promotes esophageal squamous cell carcinoma metastasis through modulating Snail stability. Oncogene. 2018;37:3356–68.

    CAS  PubMed  Google Scholar 

  50. Xiao Z, Chang L, Kim J, Zhang P, Hang Q, Yap S, et al. USP37 is a SNAI1 deubiquitinase. Am J Cancer Res. 2019;9:2749–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Aga M, Bentz GL, Raffa S, Torrisi MR, Kondo S, Wakisaka N, et al. Exosomal HIF1α supports invasive potential of nasopharyngeal carcinoma-associated LMP1-positive exosomes. Oncogene. 2014;33:4613–22.

    CAS  PubMed  Google Scholar 

  52. Zhang H, Deng T, Ge S, Liu Y, Bai M, Zhu K, et al. Exosome circRNA secreted from adipocytes promotes the growth of hepatocellular carcinoma by targeting deubiquitination-related USP7. Oncogene. 2019;38:2844–59.

    CAS  PubMed  Google Scholar 

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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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