title: Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis.
abstract: DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b-/- lymphomas, but not in Dnmt3b-/- pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b-/- lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies.
authors: Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-5950, USA.
authors: Ryan A
authors: RA
authors: Hlady
authors: Slavomira
authors: S
authors: Novakova
authors: Jana
authors: J
authors: Opavska
authors: David
authors: D
authors: Klinkebiel
authors: Staci L
authors: SL
authors: Peters
authors: Juraj
authors: J
authors: Bies
authors: Jay
authors: J
authors: Hannah
authors: Javeed
authors: J
authors: Iqbal
authors: Kristi M
authors: KM
authors: Anderson
authors: Hollie M
authors: HM
authors: Siebler
authors: Lynette M
authors: LM
authors: Smith
authors: Timothy C
authors: TC
authors: Greiner
authors: Dhundy
authors: D
authors: Bastola
authors: Shantaram
authors: S
authors: Joshi
authors: Oksana
authors: O
authors: Lockridge
authors: Melanie A
authors: MA
authors: Simpson
authors: Dean W
authors: DW
authors: Felsher
authors: Kay-Uwe
authors: KU
authors: Wagner
authors: Wing C
authors: WC
authors: Chan
authors: Judith K
authors: JK
authors: Christman
authors: Rene
authors: R
authors: Opavsky
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D008223:Lymphoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009857:Oncogenes; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation; D000097584:DNA Methyltransferase 3B
chemical_list: D004248:DNA (Cytosine-5-)-Methyltransferases; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D000097584:DNA Methyltransferase 3B