Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8)

PLoS One. 2013;8(2):e57329. doi: 10.1371/journal.pone.0057329. Epub 2013 Feb 25.

Abstract

We have identified the zinc-finger transcription factor Kruppel-like factor 4 (Klf4) among the transcription factors that are significantly downregulated in their expression during epithelial-mesenchymal transition (EMT) in mammary epithelial cells and in breast cancer cells. Loss and gain of function experiments demonstrate that the down-regulation of Klf4 expression is required for the induction of EMT in vitro and for metastasis in vivo. In addition, reduced Klf4 expression correlates with shorter disease-free survival of subsets of breast cancer patients. Yet, reduced expression of Klf4 also induces apoptosis in cells undergoing TGFβ-induced EMT. Chromatin immunoprecipitation/deep-sequencing in combination with gene expression profiling reveals direct Klf4 target genes, including E-cadherin (Cdh1), N-cadherin (Cdh2), vimentin (Vim), β-catenin (Ctnnb1), VEGF-A (Vegfa), endothelin-1 (Edn1) and Jnk1 (Mapk8). Thereby, Klf4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. Specifically, increased expression of Jnk1 (Mapk8) upon down-regulation of its transcriptional repressor Klf4 is required for EMT cell migration and for the induction of apoptosis. The data demonstrate a central role of Klf4 in the maintenance of epithelial cell differentiation and the prevention of EMT and metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Epithelial-Mesenchymal Transition / physiology*
  • Kruppel-Like Transcription Factors / physiology*
  • Mice
  • Mitogen-Activated Protein Kinase 8 / physiology*
  • Neoplasms, Experimental / pathology
  • Trans-Activators / physiology*

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors
  • Trans-Activators
  • Mitogen-Activated Protein Kinase 8

Grant support

This work was supported by the Swiss National Science Foundation, the SystemsX.ch RTD project Cellplasticity, and the Swiss Cancer League. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.