Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation

• Published in: Carcinogenesis (New York) Vol. 36; no. 7; pp. 719 - 729
• Main Authors: Hatano, Yuichiro, Semi, Katsunori, Hashimoto, Kyoichi, Lee, Myeong Sup, Hirata, Akihiro, Tomita, Hiroyuki, Kuno, Toshiya, Takamatsu, Manabu, Aoki, Koji, Taketo, Makoto M, Kim, Young-Joon, Hara, Akira, Yamada, Yasuhiro
• Format: Journal Article
• Language: English
• Published: England 01.07.2015
• Subjects: Adenomatous Polyposis Coli Protein - genetics; Animals; CDX2 Transcription Factor; Cell Differentiation - genetics; Cell Line, Tumor; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Mice, Inbred C57BL; Mice, Mutant Strains; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Promoter Regions, Genetic; Tissue Array Analysis; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgv060

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.