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

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.A.G.G. Vooijs

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1501-1510
Number of pages10
Issue number11
Publication statusPublished - 2008


  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Blotting, Western
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Cell Hypoxia
  • Cells, Cultured
  • Deferoxamine
  • Gene Expression Regulation
  • Genome
  • HeLa Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Procollagen-Proline Dioxygenase
  • RNA, Messenger
  • RNA, Small Interfering
  • Repressor Proteins
  • Response Elements
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Twist Transcription Factor


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