title: Klf4 is a transcriptional regulator of genes critical for EMT, including Jnk1 (Mapk8).
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.
authors: Department of Biomedicine, University of Basel, Basel, Switzerland.
authors: Neha
authors: N
authors: Tiwari
authors: Nathalie
authors: N
authors: Meyer-Schaller
authors: Phil
authors: P
authors: Arnold
authors: Helena
authors: H
authors: Antoniadis
authors: Mikhail
authors: M
authors: Pachkov
authors: Erik
authors: E
authors: van Nimwegen
authors: Gerhard
authors: G
authors: Christofori
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000473:pathology; D015534:Trans-Activators / Q000502:physiology*
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D015534:Trans-Activators; D048055:Mitogen-Activated Protein Kinase 8