title: Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis.
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.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Radiation Biology Core Laboratory of Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
authors.forename: Lu-Kai
authors.initials: LK
authors.lastname: Wang
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York 10065, USA.
authors.forename: Shu-Ping
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Department of Pathology and Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Yi-Liang
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Yi-Ying
authors.initials: YY
authors.lastname: Wu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hsuan-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.
authors.forename: Tzu-Hung
authors.initials: TH
authors.lastname: Hsiao
authors.affiliation: Aptamer Core, Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Wei-Yun
authors.initials: WY
authors.lastname: Lai
authors.affiliation: Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Hsuan-Hsuan
authors.initials: HH
authors.lastname: Lu
authors.affiliation: Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ya-Hsuan
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Shuenn-Chen
authors.initials: SC
authors.lastname: Yang
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 11221, Taiwan.
authors.forename: Ming-Wei
authors.initials: MW
authors.lastname: Lin
authors.affiliation: 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, Taoyuan 33303, Taiwan.
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan.|Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins; D058750:Epithelial-Mesenchymal Transition; D056284:Histone Deacetylase 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008954:Models, Biological; D018832:Molecular Chaperones; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D000072258:Tumor Hypoxia / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D025521:Tumor Suppressor Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1