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Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis

Author

Listed:
  • Ching-Wen Lin

    (Institute of Biomedical Sciences, Academia Sinica)

  • Lu-Kai Wang

    (Radiation Biology Core Laboratory of Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital)

  • Shu-Ping Wang

    (Laboratory of Biochemistry and Molecular Biology, The Rockefeller University)

  • Yih-Leong Chang

    (National Taiwan University College of Medicine)

  • Yi-Ying Wu

    (Graduate Institute of Clinical Medicine, National Cheng Kung University)

  • Hsuan-Yu Chen

    (Institute of Statistical Science, Academia Sinica)

  • Tzu-Hung Hsiao

    (Taichung Veterans General Hospital)

  • Wei-Yun Lai

    (Aptamer Core, Institute of Biomedical Sciences, Academia Sinica)

  • Hsuan-Hsuan Lu

    (National Taiwan University College of Medicine)

  • Ya-Hsuan Chang

    (Institute of Statistical Science, Academia Sinica)

  • Shuenn-Chen Yang

    (Institute of Biomedical Sciences, Academia Sinica)

  • Ming-Wei Lin

    (Program in Molecular Medicine, National Yang-Ming University and Academia Sinica)

  • Chi-Yuan Chen

    (Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology)

  • Tse-Ming Hong

    (Graduate Institute of Clinical Medicine, National Cheng Kung University)

  • Pan-Chyr Yang

    (Institute of Biomedical Sciences, Academia Sinica
    National Taiwan University College of Medicine)

Abstract

Hypoxia is a major driving force of cancer invasion and metastasis. Here we show that death domain-associated protein (Daxx) acts to negatively regulate hypoxia-induced cell dissemination and invasion by inhibiting the HIF-1α/HDAC1/Slug pathway. Daxx directly binds to the DNA-binding domain of Slug, impeding histone deacetylase 1 (HDAC1) recruitment and antagonizing Slug E-box binding. This, in turn, stimulates E-cadherin and occludin expression and suppresses Slug-mediated epithelial–mesenchymal transition (EMT) and cell invasiveness. Under hypoxic conditions, stabilized hypoxia-inducible factor (HIF)-1α downregulates Daxx expression and promotes cancer invasion, whereas re-expression of Daxx represses hypoxia-induced cancer invasion. Daxx also suppresses Slug-mediated lung cancer metastasis in an orthotopic lung metastasis mouse model. Using clinical tumour samples, we confirmed that the HIF-1α/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1α/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis.

Suggested Citation

  • Ching-Wen Lin & Lu-Kai Wang & Shu-Ping Wang & Yih-Leong Chang & Yi-Ying Wu & Hsuan-Yu Chen & Tzu-Hung Hsiao & Wei-Yun Lai & Hsuan-Hsuan Lu & Ya-Hsuan Chang & Shuenn-Chen Yang & Ming-Wei Lin & Chi-Yuan, 2016. "Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13867
    DOI: 10.1038/ncomms13867
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