The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha.

E.H. Gort, G. van Haaften, I. Verlaan, A.J. Groot, R. Plasterk, A. Shvarts, K.P.M. Suijkerbuijk, T. van Laar, E. van der Wall, V. Raman, P.J. van Diest, M. Tijsterman, M. Vooijs

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgaveArtikelWetenschappelijkpeer review

Samenvatting

Hypoxia-inducible factors (HIFs) are highly conserved transcription factors that play a crucial role in oxygen homeostasis. Intratumoral hypoxia and genetic alterations lead to HIF activity, which is a hallmark of solid cancer and is associated with poor clinical outcome. HIF activity is regulated by an evolutionary conserved mechanism involving oxygen-dependent HIFalpha protein degradation. To identify novel components of the HIF pathway, we performed a genome-wide RNA interference screen in Caenorhabditis elegans, to suppress HIF-dependent phenotypes, like egg-laying defects and hypoxia survival. In addition to hif-1 (HIFalpha) and aha-1 (HIFbeta), we identified hlh-8, gska-3 and spe-8. The hlh-8 gene is homologous to the human oncogene TWIST1. We show that TWIST1 expression in human cancer cells is enhanced by hypoxia in a HIF-2alpha-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2alpha, but not HIF-1alpha. These results identify TWIST1 as a direct target gene of HIF-2alpha, which may provide insight into the acquired metastatic capacity of hypoxic tumors.
Originele taal-2Engels
Pagina's (van-tot)1501-1510
TijdschriftOncogene
Volume27
Nummer van het tijdschrift11
DOI's
StatusGepubliceerd - 2008

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