Stimulation of the intestinal Cdx2 homeobox gene by butyrate in colon cancer cells.
BACKGROUND
The transcription factor encoded by the intestinal Cdx2 homeobox gene and treatment with sodium butyrate (NaB), a byproduct of fibre fermentation by colonic bacteria, exert similar effects on colon cancer cell lines as they both inhibit cell growth and stimulate cell differentiation and apoptosis.


OBJECTIVE
To investigate whether NaB regulates expression of the Cdx2 gene in colon cancer cell lines.


METHODS
Human adenocarcinoma cell lines Caco2 and HT29 were grown in the presence or absence of NaB. Cells were analysed for Cdx2 mRNA expression by reverse transcription-polymerase chain reaction, for protein expression by western blotting and electromobility shift assays, and for transcriptional activity of the Cdx2 promoter by transfection with luciferase reporter plasmids.


RESULTS
In HT29 and Caco2 cells, NaB stimulated Cdx2 mRNA and protein expression as well as transcriptional activity of the Cdx2 promoter. Stimulation of the activity of the Cdx2 promoter by NaB was dose and time dependent. The Cdx2 promoter contains discrete regions that participate in or inversely that blunt the stimulatory effect exerted by NaB. In addition, NaB stimulated the transcriptional activity of the Cdx2 promoter downregulated by oncogenic ras.


CONCLUSIONS
This study is the first report of an intestine specific transcription factor, Cdx2, stimulated by butyrate. Thus it provides a new mechanism whereby butyrate controls proliferation and differentiation of colon cancer cells.
Domon-Dell
C
C
Institut National de la Santé et de la Recherche Médicale, Unité 381, Strasbourg, France.
Wang
Q
Q
Kim
S
S
Kedinger
M
M
Evers
B M
BM
Freund
J-N
JN
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology*; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005801:Genes, Homeobox / Q000187:drug effects*; D011905:Genes, ras; D019073:HT29 Cells / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators
D002087:Butyrates; D000071616:CDX2 Transcription Factor; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D015534:Trans-Activators