Involvement of KLF4 in sulforaphane- and iberin-mediated induction of p21(waf1/cip1).
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.
Traka
Maria H
MH
Phytochemicals and Health Programme, Institute of Food Research, Colney, England. Maria.Traka@bbsrc.ac.uk
Chambers
Karen F
KF
Lund
Elizabeth K
EK
Goodlad
Robert A
RA
Johnson
Ian T
IT
Mithen
Richard F
RF
D000818:Animals; D001937:Brassica / Q000737:chemistry; D018938:Caco-2 Cells; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D017491:Genes, APC; D006131:Growth Inhibitors / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D013394:Sucrase-Isomaltase Complex / Q000378:metabolism; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006131:Growth Inhibitors; D017879:Isothiocyanates; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D013454:Sulfoxides; D013861:Thiocyanates; C082585:iberin; D013394:Sucrase-Isomaltase Complex; C016766:sulforaphane