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

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