Article abstract

Nature Cell Biology 10, 295 - 305 (2008)
Published online: 24 February 2008 | doi:10.1038/ncb1691

Direct regulation of TWIST by HIF-1alpha promotes metastasis

Muh-Hwa Yang1,2,3,6,9, Min-Zu Wu1,9, Shih-Hwa Chiou2,4, Po-Min Chen3,6, Shyue-Yih Chang5,6, Chung-Ji Liu7, Shu-Chun Teng8 & Kou-Juey Wu1,2,6

Stabilization of the hypoxia-inducible factor-1alpha (HIF-1alpha) transcription complex, caused by intratumoural hypoxia, promotes tumour progression and metastasis, leading to treatment failure and mortality in different types of human cancers. The transcription factor TWIST is a master regulator of gastrulation and mesoderm-specification and was implicated recently as an essential mediator of cancer metastasis. Notably, HIF-1alpha- and TWIST-null mice show similarities in their phenotypes. Here, we have shown that hypoxia or overexpression of HIF-1alpha promotes epithelial–mesenchymal transition (EMT) and metastastic phenotypes. We also found that HIF-1 regulates the expression of TWIST by binding directly to the hypoxia-response element (HRE) in the TWIST proximal promoter. However, siRNA-mediated repression of TWIST in HIF-1alpha-overexpressing or hypoxic cells reversed EMT and metastastic phenotypes. Co-expression of HIF-1alpha, TWIST and Snail in primary tumours of patients with head and neck cancers correlated with metastasis and the worst prognosis. These results provide evidence of a key signalling pathway involving HIF-1alpha and TWIST that promotes metastasis in response to intratumoural hypoxia.

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  1. Institutes of Biochemistry & Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Li-Niong Street, Peitou, Taipei 112, Taiwan.
  2. Clinical Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Niong Street, Peitou, Taipei 112, Taiwan.
  3. Division of Hematology-Oncology, Departments of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.
  4. Medical Research & Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.
  5. Otolaryngology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.
  6. Genomic Research Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.
  7. Department of Dentistry, Taipei Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei 104, Taiwan.
  8. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec, 2, Jen-Ai Road, Taipei 100, Taiwan.
  9. These authors contributed equally to this work.

Correspondence to: Kou-Juey Wu1,2,6 e-mail: kjwu2@ym.edu.tw



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