Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation

Yuichiro Hatano, Katsunori Semi, Kyoichi Hashimoto, Myeong Sup Lee, Akihiro Hirata, Hiroyuki Tomita, Toshiya Kuno, Manabu Takamatsu, Koji Aoki, Makoto M. Taketo, Young Joon Kim, Akira Hara, Yasuhiro Yamada

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14 Citations (Scopus)

Abstract

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 ApcMin/+ 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.

Original languageEnglish
Pages (from-to)719-729
Number of pages11
JournalCarcinogenesis
Volume36
Issue number7
DOIs
Publication statusPublished - 2015 Jan 1

All Science Journal Classification (ASJC) codes

  • Cancer Research

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  • Cite this

    Hatano, Y., Semi, K., Hashimoto, K., Lee, M. S., Hirata, A., Tomita, H., Kuno, T., Takamatsu, M., Aoki, K., Taketo, M. M., Kim, Y. J., Hara, A., & Yamada, Y. (2015). Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation. Carcinogenesis, 36(7), 719-729. https://doi.org/10.1093/carcin/bgv060