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, Yi Liang 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, Pan Chyr Yang

研究成果: Article

17 引文 (Scopus)

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-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.

原文English
文章編號13867
期刊Nature communications
7
DOIs
出版狀態Published - 2016 十二月 22

指紋

Histone Deacetylase 1
Hypoxia-Inducible Factor 1
Gastropoda
hypoxia
metastasis
lungs
Lung Neoplasms
cancer
Cells
Neoplasm Metastasis
Neoplasms
Occludin
Cadherins
Tumors
Cell Hypoxia
Epithelial-Mesenchymal Transition
Hypoxia
cells
DNA
death

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

引用此文

Lin, C. W., Wang, L. K., Wang, S. P., Chang, Y. L., Wu, Y. Y., Chen, H. Y., ... Yang, P. C. (2016). Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis. Nature communications, 7, [13867]. https://doi.org/10.1038/ncomms13867
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 ; Yang, Pan Chyr. / Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis. 於: Nature communications. 2016 ; 卷 7.
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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.",
author = "Lin, {Ching Wen} and Wang, {Lu Kai} and Wang, {Shu Ping} and Chang, {Yi Liang} and Wu, {Yi Ying} and Chen, {Hsuan Yu} and Hsiao, {Tzu Hung} and Lai, {Wei Yun} and Lu, {Hsuan Hsuan} and Chang, {Ya Hsuan} and Yang, {Shuenn Chen} and Lin, {Ming Wei} and Chen, {Chi Yuan} and Tse-Ming Hong and Yang, {Pan Chyr}",
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month = "12",
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Lin, CW, Wang, LK, Wang, SP, Chang, YL, Wu, YY, Chen, HY, Hsiao, TH, Lai, WY, Lu, HH, Chang, YH, Yang, SC, Lin, MW, Chen, CY, Hong, T-M & Yang, PC 2016, 'Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis', Nature communications, 卷 7, 13867. https://doi.org/10.1038/ncomms13867

Daxx inhibits hypoxia-induced lung cancer cell metastasis by suppressing the HIF-1α/HDAC1/Slug axis. / 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; Yang, Pan Chyr.

於: Nature communications, 卷 7, 13867, 22.12.2016.

研究成果: Article

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AU - Lin, Ching Wen

AU - Wang, Lu Kai

AU - Wang, Shu Ping

AU - Chang, Yi Liang

AU - Wu, Yi Ying

AU - Chen, Hsuan Yu

AU - Hsiao, Tzu Hung

AU - Lai, Wei Yun

AU - Lu, Hsuan Hsuan

AU - Chang, Ya Hsuan

AU - Yang, Shuenn Chen

AU - Lin, Ming Wei

AU - Chen, Chi Yuan

AU - Hong, Tse-Ming

AU - Yang, Pan Chyr

PY - 2016/12/22

Y1 - 2016/12/22

N2 - 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.

AB - 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.

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