Direct regulation of TWIST by HIF-1alpha promotes metastasis - PubMed (original) (raw)
. 2008 Mar;10(3):295-305.
doi: 10.1038/ncb1691. Epub 2008 Feb 24.
Affiliations
- PMID: 18297062
- DOI: 10.1038/ncb1691
Direct regulation of TWIST by HIF-1alpha promotes metastasis
Muh-Hwa Yang et al. Nat Cell Biol. 2008 Mar.
Abstract
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.
Comment in
- A hypoxic twist in metastasis.
Peinado H, Cano A. Peinado H, et al. Nat Cell Biol. 2008 Mar;10(3):253-4. doi: 10.1038/ncb0308-253. Nat Cell Biol. 2008. PMID: 18311179 No abstract available.
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