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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / secondary
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Cell Line, Tumor
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Co-Repressor Proteins
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Epithelial-Mesenchymal Transition
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Histone Deacetylase 1 / chemistry
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Histone Deacetylase 1 / genetics
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Histone Deacetylase 1 / metabolism*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / chemistry
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism*
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Lung Neoplasms / secondary*
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, Nude
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Mice, SCID
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Models, Biological
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Molecular Chaperones
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Neoplasm Invasiveness / prevention & control
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding
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Protein Interaction Domains and Motifs
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Signal Transduction
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Snail Family Transcription Factors / chemistry
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Snail Family Transcription Factors / genetics
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Snail Family Transcription Factors / metabolism*
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Transcriptome
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Tumor Hypoxia / physiology
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Co-Repressor Proteins
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DAXX protein, human
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Molecular Chaperones
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Nuclear Proteins
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SNAI1 protein, human
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Snail Family Transcription Factors
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Tumor Suppressor Proteins
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HDAC1 protein, human
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Histone Deacetylase 1