title: Krüppel-like factor 4 is involved in cell scattering induced by hepatocyte growth factor.
abstract: Hepatocyte growth factor/scatter factor (HGF) is unique by inducing epithelial cell scattering, a cellular event pivotal to HGF-mediated invasive-growth response essential for embryonic development and metastasis. Krüppel-like factor 4 (KLF4) is a multifunctional zinc-finger transcription factor involved in cell proliferation, differentiation and self-renewal. We herein present the first evidence for the functional connection between KLF4 and HGF-induced cell scattering. In particular, we found that KLF4 was upregulated by HGF in two independent epithelial cell types, HepG2 and MDCK, whereas KLF4 knockdown inhibited HGF-induced E-cadherin suppression and cell scattering. Moreover, enforced nuclear KLF4 expression alone was sufficient to upregulate KLF4, downregulate E-cadherin and trigger scattering. Chromatin immunoprecipitation (ChIP) analysis further revealed that KLF4 induced suppression of E-cadherin transcription by directly binding to the E-cadherin promoter. Additionally, we proved that HGF-induced upregulation of KLF4 transcription and cell scattering require activation of the MEK/ERK signaling pathway and the induction of early growth response 1 (EGR-1). At the mechanistic level, ChIP analysis validated a direct binding of EGR-1 to the KLF4 promoter to induce KLF4 transcription; in turn, EGR-1-induced KLF4 binds to its own promoter, thus creating a positive feedback mechanism to sustain KLF4 expression and the resultant cell scattering. We conclude that KLF4 upregulation by HGF represents a novel mechanism mediating HGF-induced cell scattering and perhaps other associated events such as cell migration and invasion.
authors.affiliation: Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Jun-Kai
authors.initials: JK
authors.lastname: Lai
authors.forename: Han-Chung
authors.initials: HC
authors.lastname: Wu
authors.forename: Yuh-Chiang
authors.initials: YC
authors.lastname: Shen
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Hsieh
authors.forename: Shu-Yi
authors.initials: SY
authors.lastname: Yang
authors.forename: Chia-Che
authors.initials: CC
authors.lastname: Chang
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics*; D004285:Dogs; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D061985:Madin Darby Canine Kidney Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics; D015398:Signal Transduction
chemical_list: D015820:Cadherins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D017228:Hepatocyte Growth Factor