Involvement of KLF4 in sulforaphane- and iberin-mediated induction of p21(waf1/cip1)

Nutr Cancer. 2009;61(1):137-45. doi: 10.1080/01635580802348641.

Abstract

Sulforaphane (SF; 4-methylsulfinylbutyl isothiocyanate), a dietary compound derived from broccoli, may exhibit chemopreventive properties by inducing cell cycle arrest via induction of cyclin-dependent kinase inhibitor 1A (p21(waf1/cip1)), but the exact molecular mechanism has not been determined. Here we evaluate the role of the transcription factor Kruppel-like factor 4 (KLF4) in mediating the induction of p21(waf1/cip1) and cellular differentiation by SF and iberin (IB; 3-methylsulphinyl propyl isothiocyanate), also derived from broccoli. Exposure of Caco-2 and Caco-2/TC7 cells to SF and IB increased expression of both KLF4 and p21(waf1/cip1), whereas exposure of HT29 cells resulted only in induction of p21(waf1/cip1). In Caco-2 cells, small interfering RNA knock down of KLF4 expression attenuated induction of p21(waf1/cip1) in response to either SF or IB treatment. Contrary to expectation, prolonged exposure to SF reduced sucrase isomaltase activity, a marker of small intestinal differentiation in Caco-2 cells. Additional support for the SF-mediated induction of p21(waf1/cip1) by KLF4 was obtained from analyses of gastric tissue of Apc(Min/+) mice following acute intervention with SF but not from the analyses of other tissue of the intestinal tract. These results suggest that induction of p21(waf1/cip1) by SF or IB may be partly mediated by KLF4 in some colon cancer cells and tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brassica / chemistry
  • Caco-2 Cells
  • Cell Cycle / drug effects*
  • Cell Differentiation
  • Cell Line
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism*
  • Genes, APC
  • Growth Inhibitors / metabolism
  • HT29 Cells
  • Humans
  • Isothiocyanates / pharmacology*
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Sucrase-Isomaltase Complex / metabolism
  • Thiocyanates / pharmacology*

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • GKLF protein
  • Growth Inhibitors
  • Isothiocyanates
  • Kruppel-Like Transcription Factors
  • Thiocyanates
  • iberin
  • Sucrase-Isomaltase Complex
  • sulforafan