title: Inhibition of DNA Methylation Suppresses Intestinal Tumor Organoids by Inducing an Anti-Viral Response.
abstract: Recent studies have proposed that the major anti-tumor effect of DNA methylation inhibitors is induction of interferon-responsive genes via dsRNAs-containing endogenous retroviruses. Recently, a 3D culture system for stem cells known as organoid culture has been developed. Lgr5-positive stem cells form organoids that closely recapitulate the properties of original tissues. To investigate the effect of DNA demethylation on tumor organoids, we have established organoids from intestinal tumors of Apc(Min/+) (Min) mice and subjected them to 5-aza-2'-deoxycytidine (5-Aza-CdR) treatment and Dnmt1 knockdown. DNA demethylation induced by 5-Aza-CdR treatment and Dnmt1 knockdown significantly reduced the cell proliferation of the tumor organoids. Microarray analyses of the tumor organoids after 5-Aza-CdR treatment and Dnmt1 knockdown revealed that interferon-responsive genes were activated by DNA demethylation. Gene ontology and pathway analyses clearly demonstrated that these genes activated by DNA demethylation are involved in the anti-viral response. These findings indicate that DNA demethylation suppresses the proliferation of intestinal tumor organoids by inducing an anti-viral response including activation of interferon-responsive genes. Treatment with DNA methylation inhibitors to activate a growth-inhibiting immune response may be an effective therapeutic approach for colon cancers.
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakaoka
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Kasumi
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Muramatsu
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Toshimitsu
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Pharmacotherapeutics, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan.|Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Saito
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D007113:Immunity, Innate / Q000187:drug effects*; D051379:Mice; D046228:Microarray Analysis; D009940:Organoids / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619381:Dnmt1 protein, mouse; D001374:Azacitidine