CDX transcription factors positively regulate expression of solute carrier family 5, member 8 in the colonic epithelium.
OBJECTIVE
Caudal-related homeodomain transcription factors CDX1 and CDX2 regulate gut development and differentiation of intestinal epithelial cells; they are candidate tumor suppressors of colorectal carcinomas. Because the functions of CDX1 and CDX2 in the colonic epithelium are not fully understood, we sought to identify genes that they target.


METHODS
We conducted a chromatin immunoprecipitation (ChIP) screen to identify genes that bind the CDX transcription factors. Expression of target genes was analyzed in colon cells and tissues from Cdx1(-/-), Cdx2(+/-), Apc(+/Delta716), and wild-type (control) mice.


RESULTS
Using the ChIP screen, we identified solute carrier family 5, member 8 (SLC5A8, also known as SMCT1) as a direct target of CDX1 and CDX2. CDX transcription factors bind to the promoter region of SLC5A8 and transactivate SLC5A8 reporter constructs. Overexpression of Cdx1 or Cdx2 in human colon cancer cell lines induced expression of endogenous SLC5A8, whereas CDX1 and CDX2 knockdowns reduced its level. Consistently, Slc5a8 expression was significantly reduced in colons of Cdx1(-/-) or Cdx2(+/-) mice compared with wild-type mice. Slc5a8 levels were also reduced in colonic adenomatous polyps and hamartomas from Apc(+/Delta716) and Cdx2(+/-) mutant mice, respectively, compared with adjacent normal colon tissues.


CONCLUSIONS
CDX1 and CDX2 bind the promoter region of SLC5A8 and up-regulate its expression in cultured cells and in colonic epithelium. SLC5A8 transports monocarboxylates such as pyruvate, lactate, and butyrate; CDX1 and CDX2 might therefore regulate the uptake of these substances in the colon.
Kakizaki
Fumihiko
F
Department of Pharmacology, Graduate School of Medicine, Kyoto University, Sakyo, Kyoto, Japan.
Aoki
Koji
K
Miyoshi
Hiroyuki
H
Carrasco
Nancy
N
Aoki
Masahiro
M
Taketo
Makoto M
MM
D000818:Animals; D000071616:CDX2 Transcription Factor; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D027501:Monocarboxylic Acid Transporters; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; D027682:Cation Transport Proteins; C491272:Cdx1 protein, mouse; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D027501:Monocarboxylic Acid Transporters; C507459:Slc5a8 protein, mouse; D014157:Transcription Factors