Krüppel-like factor 4 regulates stemness and mesenchymal properties of colorectal cancer stem cells through the TGF-β1/Smad/snail pathway

J Cell Mol Med. 2020 Jan;24(2):1866-1877. doi: 10.1111/jcmm.14882. Epub 2019 Dec 12.

Abstract

Krüppel-like factor 4 (KLF4) was closely associated with epithelial-mesenchymal transition and stemness in colorectal cancer stem cells (CSCs)-enriched spheroid cells. Nonetheless, the underlying molecular mechanism is unclear. This study showed that KLF4 overexpression was accompanied with stemness and mesenchymal features in Lgr5+ CD44+ EpCAM+ colorectal CSCs. KLF4 knockdown suppressed stemness, mesenchymal features and activation of the TGF-β1 pathway, whereas enforced KLF4 overexpression activated TGF-β1, phosphorylation of Smad 2/3 and Snail expression, and restored stemness and mesenchymal phenotypes. Furthermore, TGF-β1 pathway inhibition invalidated KLF4-facilitated stemness and mesenchymal features without affecting KLF4 expression. The data from the current study are the first to demonstrate that KLF4 maintains stemness and mesenchymal properties through the TGF-β1/Smad/Snail pathway in Lgr5+ CD44+ EpCAM+ colorectal CSCs.

Keywords: Krüppel-like factor 4; TGF-β1; cancer stem cell; colorectal cancer; snail.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Epithelial Cell Adhesion Molecule / metabolism
  • Humans
  • Hyaluronan Receptors / metabolism
  • Imidazoles / pharmacology
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / metabolism*
  • Mesoderm / pathology*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • Quinoxalines / pharmacology
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction* / drug effects
  • Smad Proteins / metabolism*
  • Snail Family Transcription Factors / metabolism*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • 6-(2-tert-butyl-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline
  • CD44 protein, human
  • Epithelial Cell Adhesion Molecule
  • Hyaluronan Receptors
  • Imidazoles
  • KLF4 protein, human
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • LGR5 protein, human
  • Quinoxalines
  • Receptors, G-Protein-Coupled
  • Smad Proteins
  • Snail Family Transcription Factors
  • Transforming Growth Factor beta1