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

• Published in: Nature communications Vol. 7; no. 1; p. 13867
• Main Authors: Lin, Ching-Wen, Wang, Lu-Kai, Wang, Shu-Ping, Chang, Yih-Leong, 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, Yang, Pan-Chyr
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14/19; 59/5; 631/67; 631/80/84; 64/60; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - secondary; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Histone Deacetylase 1 - chemistry; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Humanities and Social Sciences; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - chemistry; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Male; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Models, Biological; multidisciplinary; Neoplasm Invasiveness - prevention & control; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Protein Binding; Protein Interaction Domains and Motifs; Science; Science (multidisciplinary); Signal Transduction; Snail Family Transcription Factors - chemistry; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Transcriptome; Tumor Hypoxia - physiology; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13867

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. Hypoxia and epithelial-to-mesenchymal transition promotes cancer metastasis. Here the authors show that Daxx inhibits hypoxia-induced lung cancer metastasis by attenuating Slug-mediated transcriptional repression of epithelial-like markers that in turn cause cells to exhibit low invasiveness.