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

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 Chen, Tse-Ming Hong () and Pan-Chyr Yang ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13867

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