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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1501-1510
Number of pages10
JournalOncogene
Volume27
Issue number11
DOIs
StatePublished - Mar 6 2008

Keywords

  • C. elegans
  • Cancer
  • HIF-2α
  • Hypoxia
  • TWIST1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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