Direct regulation of TWIST by HIF-1alpha promotes metastasis.
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.
Yang
Muh-Hwa
MH
Institutes of Biochemistry & Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Li-Niong Street, Peitou, Taipei 112, Taiwan.
Wu
Min-Zu
MZ
Chiou
Shih-Hwa
SH
Chen
Po-Min
PM
Chang
Shyue-Yih
SY
Liu
Chung-Ji
CJ
Teng
Shu-Chun
SC
Wu
Kou-Juey
KJ
D002450:Cell Communication; D002454:Cell Differentiation; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010641:Phenotype; D011379:Prognosis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000096:biosynthesis*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1