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

Neha Tiwari1, Nathalie Meyer-Schaller, Phil Arnold

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

Plos One
|March 2, 2013
PubMed

Insights

Kruppel-like factor 4 (Klf4) is downregulated in breast cancer, promoting metastasis. Reduced Klf4 expression is linked to poor survival but also induces apoptosis, highlighting its complex role in cancer progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Epithelial-mesenchymal transition (EMT) is crucial for cancer metastasis.
  • Transcription factors play key roles in regulating EMT.
  • Kruppel-like factor 4 (Klf4) is a zinc-finger transcription factor with known roles in cell differentiation.

Purpose of the Study:

  • To investigate the role of Klf4 in EMT and breast cancer metastasis.
  • To identify direct Klf4 target genes involved in EMT.
  • To elucidate the mechanism by which Klf4 regulates epithelial and mesenchymal phenotypes.

Main Methods:

  • Loss and gain of function experiments in mammary epithelial and breast cancer cells.
  • Analysis of Klf4 expression in relation to patient survival data.
  • Chromatin immunoprecipitation/deep-sequencing (ChIP-seq) combined with gene expression profiling.
  • TGFβ-induced EMT models.

Main Results:

  • Klf4 expression is significantly downregulated during EMT and in breast cancer.
  • Downregulation of Klf4 is necessary for EMT induction and metastasis.
  • Reduced Klf4 expression correlates with shorter disease-free survival in some breast cancer patients.
  • Klf4 directly regulates genes involved in epithelial (e.g., E-cadherin) and mesenchymal (e.g., N-cadherin, vimentin) phenotypes.
  • Klf4 represses Jnk1 (Mapk8) expression, which is required for EMT cell migration and apoptosis.

Conclusions:

  • Klf4 acts as a crucial suppressor of EMT and metastasis in breast cancer.
  • Klf4 maintains epithelial cell differentiation by activating epithelial genes and repressing mesenchymal genes.
  • The complex role of Klf4 in regulating apoptosis during EMT warrants further investigation.

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