title: HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions.
abstract: The WASF3 (WAVE3) gene is an important mediator of cell motility, invasion and metastasis and is expressed at high levels in some advanced stage tumors. In our survey of breast cancer cells, we now demonstrate that exposure to hypoxic conditions increases WASF3 expression levels in MDA231, SKBR3 and MCF7 cells. The WASF3 promoter region contains HIF1A response elements (HRE). ChIP assays demonstrate that HIF1A binds to these HRE elements in the promoter region, and luciferase reporter assays using the WASF3 gene minimal promoter shows that hypoxia results in its upregulation. Phosphorylation of WASF3 is required for its ability to affect invasion and increased phosphoactivation of WASF3 is also seen in cells challenged with hypoxia. These cells also show increased motility in the scratch wound assay. Cells in which WASF3 has been knocked down show no response to hypoxia as expected, implicating the specificity of the hypoxic response to WASF3. Overall, these experiments demonstrate WASF3 is a HIF1A-regulated gene and suggests a mechanism to explain the observation of elevated expression of WASF3 in advanced stage tumors.
authors.affiliation: Georgia Health Sciences University Cancer Center, Augusta, GA 30912, USA.
authors.forename: Pushpankur
authors.initials: P
authors.lastname: Ghoshal
authors.forename: Yong
authors.initials: Y
authors.lastname: Teng
authors.forename: Leslie Ann
authors.initials: LA
authors.lastname: Lesoon
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000494:pharmacology; D014158:Transcription, Genetic; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics* / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; C120153:WASF3 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family; C116890:Semaxinib