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Impairment of DYRK2 augments stem-like traits by promoting KLF4 expression in breast cancer

Oncogene volume 36, pages 1862–1872 (2017)Cite this article

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Abstract

Whereas accumulating studies have supported the cancer stem cell theory, a specific therapy targeting a cancer stem cell subpopulation has not been established. Here, we show that dual-specificity tyrosine phosphorylation-kinase 2 (DYRK2) is a novel negative regulator for formation of breast cancer stem cells. Downregulation of DYRK2 promotes cancer stem-like traits in vitro, tumourigenesis in vivo and the proportion of the cancer stem cell population in human breast cancer tissues. We found that Krupple-like factor 4 (KLF4) serves as a key mediator of DYRK2’s control over the cancer stem phenotype. Reduced DYRK2 expression increases KLF4 expression, which induces cancer stem-like properties. We identified androgen receptor (AR) as a transcription factor binding to the KLF4 promoter region; this process is dependent on DYRK2 kinase activity. Our findings delineate a mechanism of cancer stem cell regulation by the DYRK2–AR–KLF4 axis in breast cancer. Targeting of this pathway may be a promising strategy against breast cancer stem cells.

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Acknowledgements

The authors appreciate all patients who provided the clinical samples for the study. We thank Naoe T Nihira for microarray analysis, Mamiko Owada for immunohistochemistry, Minori Kamada for FACS analysis and Noriko Yamaguchi for xenograft experiments. This work was supported by grants from JSPS KAKENHI Grant Number 26290041 and 26861056, Takeda Science Foundation, the Vehicle Racing Commemorative Foundation and Research Grant of the Princess Takamatsu Cancer Research Fund.

Author contributions

RM and KY designed the research. RM and YI performed the research. SH analyzed the immunohistochemistry. HT provided the breast cancer specimens and analyzed clinical data. KY supervised the research. RM, YI and KY wrote the manuscript.

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Author notes

  1. R Mimoto and Y Imawari: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Jikei University School of Medicine, Tokyo, Japan

    R Mimoto, Y Imawari & K Yoshida

  2. Department of Surgery, Jikei University School of Medicine, Tokyo, Japan

    R Mimoto, Y Imawari & H Takeyama

  3. Department of Pathology, Jikei University School of Medicine, Tokyo, Japan

    S Hirooka

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  1. R Mimoto
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  2. Y Imawari
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  5. K Yoshida
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Corresponding author

Correspondence to K Yoshida.

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The authors declare no conflict of interest.

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Mimoto, R., Imawari, Y., Hirooka, S. et al. Impairment of DYRK2 augments stem-like traits by promoting KLF4 expression in breast cancer. Oncogene 36, 1862–1872 (2017). https://doi.org/10.1038/onc.2016.349

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  • DOI: https://doi.org/10.1038/onc.2016.349

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