Reducing DNA methylation suppresses colon carcinogenesis by inducing tumor cell differentiation. 2015

Yuichiro Hatano, and Katsunori Semi, and Kyoichi Hashimoto, and Myeong Sup Lee, and Akihiro Hirata, and Hiroyuki Tomita, and Toshiya Kuno, and Manabu Takamatsu, and Koji Aoki, and Makoto M Taketo, and Young-Joon Kim, and Akira Hara, and Yasuhiro Yamada
Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.

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.

UI MeSH Term Description Entries
D008810 Mice, Inbred C57BL One of the first INBRED MOUSE STRAINS to be sequenced. This strain is commonly used as genetic background for transgenic mouse models. Refractory to many tumors, this strain is also preferred model for studying role of genetic variations in development of diseases. Mice, C57BL,Mouse, C57BL,Mouse, Inbred C57BL,C57BL Mice,C57BL Mice, Inbred,C57BL Mouse,C57BL Mouse, Inbred,Inbred C57BL Mice,Inbred C57BL Mouse
D008817 Mice, Mutant Strains Mice bearing mutant genes which are phenotypically expressed in the animals. Mouse, Mutant Strain,Mutant Mouse Strain,Mutant Strain of Mouse,Mutant Strains of Mice,Mice Mutant Strain,Mice Mutant Strains,Mouse Mutant Strain,Mouse Mutant Strains,Mouse Strain, Mutant,Mouse Strains, Mutant,Mutant Mouse Strains,Mutant Strain Mouse,Mutant Strains Mice,Strain Mouse, Mutant,Strain, Mutant Mouse,Strains Mice, Mutant,Strains, Mutant Mouse
D011401 Promoter Regions, Genetic DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes. rRNA Promoter,Early Promoters, Genetic,Late Promoters, Genetic,Middle Promoters, Genetic,Promoter Regions,Promoter, Genetic,Promotor Regions,Promotor, Genetic,Pseudopromoter, Genetic,Early Promoter, Genetic,Genetic Late Promoter,Genetic Middle Promoters,Genetic Promoter,Genetic Promoter Region,Genetic Promoter Regions,Genetic Promoters,Genetic Promotor,Genetic Promotors,Genetic Pseudopromoter,Genetic Pseudopromoters,Late Promoter, Genetic,Middle Promoter, Genetic,Promoter Region,Promoter Region, Genetic,Promoter, Genetic Early,Promoter, rRNA,Promoters, Genetic,Promoters, Genetic Middle,Promoters, rRNA,Promotor Region,Promotors, Genetic,Pseudopromoters, Genetic,Region, Genetic Promoter,Region, Promoter,Region, Promotor,Regions, Genetic Promoter,Regions, Promoter,Regions, Promotor,rRNA Promoters
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D003110 Colonic Neoplasms Tumors or cancer of the COLON. Cancer of Colon,Colon Adenocarcinoma,Colon Cancer,Cancer of the Colon,Colon Neoplasms,Colonic Cancer,Neoplasms, Colonic,Adenocarcinoma, Colon,Adenocarcinomas, Colon,Cancer, Colon,Cancer, Colonic,Cancers, Colon,Cancers, Colonic,Colon Adenocarcinomas,Colon Cancers,Colon Neoplasm,Colonic Cancers,Colonic Neoplasm,Neoplasm, Colon,Neoplasm, Colonic,Neoplasms, Colon
D004248 DNA (Cytosine-5-)-Methyltransferases Enzymes that catalyzes the transfer of a methyl group from S-ADENOSYLMETHIONINE to the 5-position of CYTOSINE residues in DNA. DNA (Cytosine-5-)-Methyltransferase,DNA Cytosine-5-Methylase,DNA (Cytosine 5) Methyltransferase,Cytosine-5-Methylase, DNA,DNA Cytosine 5 Methylase
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000071616 CDX2 Transcription Factor An antennapedia-like homeodomain transcription factor that regulates the expression of multiple genes in the INTESTINAL MUCOSA. It plays a critical role in many processes from early differentiation to maintenance of the intestinal epithelial lining of both the small and large intestine. CDX2 Protein,Caudal Type Homeo Box 2 Protein,Caudal Type Homeo Box Transcription Factor 2,Caudal Type Homeobox Transcription Factor 2,Cdx-2 Protein,Cdx-2-3 Protein,Cdx-3 Protein,Homeobox Protein CDX-2,Homeobox Protein CDX2,Transcription Factor CDX2,CDX-2, Homeobox Protein,CDX2, Homeobox Protein,CDX2, Transcription Factor,Cdx 2 3 Protein,Cdx 2 Protein,Cdx 3 Protein,Homeobox Protein CDX 2
D000076123 DNA (Cytosine-5-)-Methyltransferase 1 A DNA (cytosine-5-)-methyltransferase that contains a central CxxC type zinc finger motif. It binds poly(ADP)-ribose and its expression is regulated by POLY (ADP-RIBOSE) POLYMERASE-1. DNMT1 methylates CpG residues, with a preference for hemimethylated DNA, and associates with DNA replication sites in S PHASE to maintain the methylation pattern in the newly synthesized strand, which is essential for EPIGENETIC PROCESSES. It also associates with CHROMATIN during G2 PHASE and MITOSIS to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns established in development; mutations in the DNMT1 gene are associated with HEREDITARY SENSORY NEUROPATHY TYPE 1 class E. DNMT1 Enzyme,Enzyme, DNMT1
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia

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