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

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Article number13867
JournalNature communications
Volume7
DOIs
Publication statusPublished - 2016 Dec 22

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General
  • General Physics and Astronomy

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