Direct regulation of TWIST by HIF-1alpha promotes metastasis

Nat Cell Biol. 2008 Mar;10(3):295-305. doi: 10.1038/ncb1691. Epub 2008 Feb 24.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Communication
  • Cell Differentiation
  • Cell Hypoxia
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / biosynthesis*
  • Neoplasm Metastasis
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Nuclear Proteins / biosynthesis*
  • Phenotype
  • Prognosis
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism
  • Twist-Related Protein 1 / biosynthesis*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Snail Family Transcription Factors
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1