The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2alpha.
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.
Gort
E H
EH
Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands.
van Haaften
G
G
Verlaan
I
I
Groot
A J
AJ
Plasterk
R H A
RH
Shvarts
A
A
Suijkerbuijk
K P M
KP
van Laar
T
T
van der Wall
E
E
Raman
V
V
van Diest
P J
PJ
Tijsterman
M
M
Vooijs
M
M
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015153:Blotting, Western; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005786:Gene Expression Regulation; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D029742:Caenorhabditis elegans Proteins; D003676:Deferoxamine; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011393:Procollagen-Proline Dioxygenase; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C103173:TWIST1 protein, human