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Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer

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Abstract

Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT) play an important role in the metastasis and chemoresistance in the context of colorectal cancer (CRC). Downregulation of death associated protein kinase 1 (DAPK1) may promote metastasis and chemoresistance of cancer cells through various mechanisms. However, the association between DAPK1 and CSCs or EMT has not been explored. In this study, we demonstrated that DAPK1 was associated with elevated stemness of CSCs in patients with CRC. Silencing of DAPK1 in CRC cell lines promoted the metastasis and chemoresistance due to increased stemness of CSCs and enhanced mesenchymal phenotype, an effect that was mediated via activation of the transcription factor, zinc finger E-box binding homeobox 1 (ZEB1). Blockade of this signaling pathway attenuated the stemness of CSCs and rescued the EMT process. DAPK1–ZEB1 may lie at the interface of TGF-β and WNT pathways and participate in both CSCs and EMT process. Targeted therapies aimed at DAPK1–ZEB1 pathway may inhibit the chemoresistance and metastasis of CRC.

Key messages

  • Downregulation of DAPK1 promotes chemoresistance and metastasis of CRC.

  • Inhibition of DAPK1 promotes the stemness of cancer stem cells and EMT process.

  • DAPK1–ZEB1 may lie at the interface of TGF-β and WNT pathways.

  • DAPK1–ZEB1 participates in both CSCs and EMT process.

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Acknowledgements

We thank Medjaden Bioscience Limited (Hong Kong, China) for proofreading this manuscript.

Funding

This study was supported by the National Nature Science Foundation of China (grant number 81470789, and 81271199), and Research Fund of Public welfare in Health Industry (grant number 201402015). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. Wenzheng Yuan and Jintong Ji contributed equally to this work.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Wenzheng Yuan, Jintong Ji, Liang Wu, Zili Zhou, Zhengyi Liu, Qiang Tang, Xudan Zhang & Xiaogang Shu

  2. Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Wenzheng Yuan

  3. College of Clinical Medicine, Hubei University of Science and Technology, Xianning, 437100, China

    Yan Shu

  4. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Jinhuang Chen

  5. Department of Hepatobiliary Surgery, The Second Hospital, Hebei Medical University, Shijiazhuang, 050000, China

    Sanguang Liu

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  1. Wenzheng Yuan
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  3. Yan Shu
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Correspondence to Xiaogang Shu.

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The study was approved by the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology (Wuhan China). Written informed consent was obtained from all participants in accordance with the guidelines in The Declaration of Helsinki 2000. All mouse experiments were conducted with approval of the Institutional Animal Care and Treatment Committee of Tongji Medical College of Huazhong University of Science and Technology, China.

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The authors declare that they have no competing interest.

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Yuan, W., Ji, J., Shu, Y. et al. Downregulation of DAPK1 promotes the stemness of cancer stem cells and EMT process by activating ZEB1 in colorectal cancer. J Mol Med 97, 89–102 (2019). https://doi.org/10.1007/s00109-018-1716-8

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  • DOI: https://doi.org/10.1007/s00109-018-1716-8

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