WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells

Oncogene. 2014 Jan 9;33(2):203-11. doi: 10.1038/onc.2012.565. Epub 2013 Jan 14.


The WASF3 gene promotes invasion and metastasis in breast cancer cells, which have undergone epithelial-to-mesenchyme transition (EMT). Overexpression of WASF3 in cells that do not show EMT increases their invasion potential as a result of increased ZEB1/2 levels, which specifically suppress the anti-invasion chromosome 1 miR-200a/200b/429 cluster. ZEB1/2 upregulation by WASF3 results from downregulation of KISS1, leading to the release of inhibition of nuclear factor (NF)κB by IκBα. We further show that ZEB1 expression is regulated by the NFκB transcription factor. Knockdown of WASF3 in breast cancer cells leads to reduced ZEB1 levels and increased miR-200 and E-cadherin levels, resulting in loss of invasion potential. The central regulation of this interactive pathway by WASF3 accounts for the increased invasion associated with increased WASF3 expression seen in aggressive breast cancer cells. WASF3, therefore, is a potential target to suppress invasion and metastasis in breast cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Breast Neoplasms / pathology*
  • Cell Adhesion
  • Cell Line, Tumor
  • Female
  • Homeodomain Proteins / physiology*
  • Humans
  • Kisspeptins / antagonists & inhibitors
  • Kisspeptins / physiology*
  • MicroRNAs / physiology*
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Promoter Regions, Genetic
  • Transcription Factors / physiology*
  • Wiskott-Aldrich Syndrome Protein Family / physiology*
  • Zinc Finger E-box-Binding Homeobox 1


  • Homeodomain Proteins
  • KISS1 protein, human
  • Kisspeptins
  • MIRN200 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Transcription Factors
  • WASF3 protein, human
  • Wiskott-Aldrich Syndrome Protein Family
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1