HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions

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...

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Bibliographic Details
Published in:International journal of cancer 2012-09, Vol.131 (6), p.E905-E915
Main Authors: Ghoshal, Pushpankur, Teng, Yong, Lesoon, Leslie Ann, Cowell, John K.
Format: Article
Language:English
Subjects:
Breast cancer
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cancer
Cell Hypoxia
Female
Gene expression
Gene Expression Regulation, Neoplastic
HIF1A
Humans
Hypoxia
Hypoxia-Inducible Factor 1, alpha Subunit - physiology
Indoles - pharmacology
invasion
Medical research
Metastasis
Motility
Neoplasm Metastasis
Pyrroles - pharmacology
Transcription, Genetic
Tumor Microenvironment
Vascular Endothelial Growth Factor A - antagonists & inhibitors
WASF3
Wiskott-Aldrich Syndrome Protein Family - genetics
Wiskott-Aldrich Syndrome Protein Family - physiology
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Summary: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.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.27631