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Wnt5a-induced docking of Plk1 on HEF1 promotes HEF1 translocation and tumorigenesis

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Abstract

Background

Upregulation of human enhancer filamentation 1 (HEF1/NEDD9/Cas-L) and Polo-like kinase 1 (Plk1) is closely correlated with metastasis of human cancer. However, the mechanism by which the overexpression of HEF1 or Plk1 stimulates cancer metastasis and induces tumorigenesis remains enigmatic. In addition, the accumulation of HEF1 at the focal adhesion (FA) is known to be an essential event in cancer cell migration, but the mechanism of how HEF1 is targeted to the FA remains yet to be unveiled.

Objective

This study was performed to elucidate the FA docking mechanism of HEF1 and to determine its effect on tumorigenesis.

Methods

To confirm the effect of the kinase on HEF1 translocation, various expression-knockdown stable cell lines were generated using a lentivirus system, and the effect of the HEF1-Plk1 complex on tumorigenesis was confirmed using a xenograft mouse model.

Results

Here, we show that Wnt5a-dependent Plk1 binding to HEF1 is critically required for HEF1 translocation to the FA. We also confirmed that Plk1 and CK1δ activities essential for HEF1 translocation are induced by Wnt5a. Finally, we confirmed the induction of tumorigenesis by the HEF1-Plk1 complex in the xenograft mouse model.

Conclusion

Our data collectively unveil the Wnt5a-CK1δ-HEF1-Plk1-FA remodeling pathway that governs HEF1 transportation to the FA to induce cell migration and tumorigenesis. This study sheds light on a mechanism underlying tumorigenesis and provides new strategies for anticancer therapy.

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Acknowledgements

We thank Kyung S. Lee, Sean B. Lee, Chou-Zen Giam, Michael B. Yaffe, and Joel Raingeaud for reagents. This work was supported by Regional Innovation Strategy (RIS) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE), the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2021R1A2C1004854), R&D Convergence Program (CAP-16-03-KRIBB) of National Research Council of Science & Technology (NST) of Republic of Korea, and KRIBB Research Initiative Program.

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Author notes

  1. Jeong-Ah Hwang, Ji Eun Yu have contributed equally to this work.

Authors and Affiliations

  1. Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang, Cheongwon, Chungbuk, 28116, South Korea

    Jeong-Ah Hwang, Ji Eun Yu, Sun-Ok Kim, Dong Hyun Kim & Kyung Ho Lee

  2. Department of Anatomy, College of Medicine, Research Institute of Medical Sciences, Chungnam National University, Daejeon, South Korea

    Jeong-Ah Hwang

  3. College of Pharmacy & Medical Research Center, Chungbuk National University, Chungbuk, 28160, South Korea

    Ji Eun Yu

  4. Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05029, South Korea

    Kyoung Sang Cho

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  1. Jeong-Ah Hwang
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  2. Ji Eun Yu
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  3. Sun-Ok Kim
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  4. Dong Hyun Kim
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Correspondence to Kyoung Sang Cho or Kyung Ho Lee.

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The authors declare that they have no conflict of interest.

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Animal studies were carried out in accordance with the institutional guidelines approved by the Institutional Animal Care and Use Committee of KRIBB (KRIBB-AEC-14082).

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Hwang, JA., Yu, J.E., Kim, SO. et al. Wnt5a-induced docking of Plk1 on HEF1 promotes HEF1 translocation and tumorigenesis. Genes Genom 43, 567–575 (2021). https://doi.org/10.1007/s13258-021-01088-x

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  • DOI: https://doi.org/10.1007/s13258-021-01088-x

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