Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation.
The forced reduction of global DNA methylation suppresses tumor development in several cancer models in vivo. Nevertheless, the mechanisms underlying these suppressive effects remain unclear. In this report, we describe our findings showing that a genome-wide reduction in the DNA methylation levels induces cellular differentiation in association with decreased cell proliferation in Apc (Min/+) mouse colon tumor cells in vivo. Colon tumor-specific DNA methylation at Cdx1 is reduced in the DNA-hypomethylated tumors accompanied by Cdx1 derepression and an increased expression of intestinal differentiation-related genes. Furthermore, a histological analysis revealed that Cdx1 derepression in the DNA-hypomethylated tumors is correlated with the differentiation of colon tumor cells. Similarly, the treatment of human colon cancer cell lines with a hypomethylating agent induces differentiation-related genes, including CDX1. We herein propose that DNA demethylation exerts a tumor suppressive effect in the colon by inducing tumor cell differentiation.
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Yuichiro
Y
Hatano
Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
Katsunori
K
Semi
Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan.
Kyoichi
K
Hashimoto
Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, 138-736, Korea.
Myeong Sup
MS
Lee
Division of Animal Experiment, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan.
Akihiro
A
Hirata
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Hiroyuki
H
Tomita
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Toshiya
T
Kuno
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Manabu
M
Takamatsu
Division of Pharmacology, University of Fukui School of Medicine, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193, Japan.
Koji
K
Aoki
Department of Pharmacology, Kyoto University Graduate School of Medicine, Sakyo, Kyoto 606-8507, Japan and.
Makoto M
MM
Taketo
Department of Integrated Omics for Biomedical Sciences, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea.
Young-Joon
YJ
Kim
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Akira
A
Hara
Center for iPS Cell Research and Application (CiRA), Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto 606-8507, Japan, y-yamada@cira.kyoto-u.ac.jp.
Yasuhiro
Y
Yamada
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D025601:Adenomatous Polyposis Coli Protein; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491272:Cdx1 protein, mouse; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D063151:Polycomb Repressive Complex 2