https://scholars.lib.ntu.edu.tw/handle/123456789/191025
標題: | Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis | 作者: | Lin, Ching-Wen Wang, Lu-Kai Wang, Shu-Ping Chang, Yi-Liang Wu, Yi-Ying Chen, Hsuan-Yu Hsiao, Tzu-Hung Lai, Wei-Yun Lu, Hsuan-Hsuan Chang, Ya-Hsuan Yang, Shuenn-Chen Lin, Ming-Wei Chen, Chi-Yuan Hong, Tse-Ming PAN-CHYR YANG |
公開日期: | 2016 | 期: | 7 | 起(迄)頁: | - | 來源出版物: | Nat. Commun. | 摘要: | 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-1 alpha/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)-1 alpha 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-1 alpha/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1 alpha/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/278807 | DOI: | 10.1038/ncomms13867 | SDG/關鍵字: | Daxx protein; histone deacetylase 1; hypoxia inducible factor 1alpha; messenger RNA; occludin; transcription factor Slug; uvomorulin; DAXX protein, human; HDAC1 protein, human; HIF1A protein, human; histone deacetylase 1; hypoxia inducible factor 1alpha; nuclear protein; protein binding; signal transducing adaptor protein; SNAI1 protein, human; transcription factor Snail; transcriptome; tumor suppressor protein; cancer; cells and cell components; enzyme activity; gene expression; hypoxia; inhibition; numerical model; protein; rodent; tumor; animal experiment; animal model; animal tissue; Article; cancer patient; cancer prognosis; cancer survival; cellular distribution; comparative study; controlled study; down regulation; E box element; epithelial mesenchymal transition; gene expression; human; human cell; human tissue; hypoxia; in vivo study; lung cancer cell line; lung carcinogenesis; lung metastasis; major clinical study; male; metastasis inhibition; migration inhibition; mouse; non small cell lung cancer; nonhuman; overall survival; promoter region; protein expression; protein function; protein protein interaction; signal transduction; transcription regulation; tumor invasion; zinc finger motif; animal; Bagg albino mouse; biological model; chemistry; genetics; lung tumor; metabolism; nonobese diabetic mouse; nude mouse; physiology; prevention and control; protein domain; SCID mouse; secondary; tumor cell line; tumor hypoxia; tumor invasion; Adaptor Proteins, Signal Transducing; Animals; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Histone Deacetylase 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Models, Biological; Neoplasm Invasiveness; Nuclear Proteins; Protein Binding; Protein Interaction Domains and Motifs; Signal Transduction; Snail Family Transcription Factors; Transcriptome; Tumor Hypoxia; Tumor Suppressor Proteins |
顯示於: | 醫學系 |
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