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

Oncogene volume 27, pages 1501–1510 (2008)Cite this article

Abstract

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 HIFα 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 (HIFα) and aha-1 (HIFβ), 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-2α-dependent manner. Furthermore, intronic hypoxia response elements of TWIST1 are regulated by HIF-2α, but not HIF-1α. These results identify TWIST1 as a direct target gene of HIF-2α, which may provide insight into the acquired metastatic capacity of hypoxic tumors.

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Acknowledgements

This work was supported by a program grant from the Dutch Cancer Foundation (KWF Kankerbestrijding, UU2003-2825) and an AEGON International Scholarship in Oncology. Additional financial support was obtained from the Maurits and Anna de Kock Foundation, the Jan Dekker and Dr Ludgardine Bouwman Foundation and the Nijbakker-Morra Foundation. We acknowledge the Caenorhabditis Genetics Center, the Ratcliffe lab and the Powell-Coffman lab for providing strains and information.

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Authors and Affiliations

  1. Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands

    E H Gort, I Verlaan, A J Groot, A Shvarts, K P M Suijkerbuijk, T van Laar, P J van Diest & M Vooijs

  2. Hubrecht Laboratory, Center for Biomedical Genetics, Utrecht, The Netherlands

    G van Haaften, R H A Plasterk & M Tijsterman

  3. Department of Medical Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands

    E van der Wall

  4. Department of Radiology, Johns Hopkins University-School of Medicine, Baltimore, MD, USA

    V Raman

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  1. E H Gort
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Gort, E., van Haaften, G., Verlaan, I. et al. The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α. Oncogene 27, 1501–1510 (2008). https://doi.org/10.1038/sj.onc.1210795

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