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

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

Author information

1
Department of Biomedicine, University of Basel, Basel, Switzerland.

Erratum in

  • PLoS One. 2013;8(10). doi:10.1371/annotation/121b04a1-0cbb-4e24-8a63-fc9cdd31ec76.

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.

PMID:
23451207
PMCID:
PMC3581489
DOI:
10.1371/journal.pone.0057329
[Indexed for MEDLINE]
Free PMC Article

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