Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

Authors

Ryan A. Hlady, University of Nebraska Medical Center
Slavomira Novakova, University of Nebraska Medical Center
Jana Opavska, University of Nebraska Medical Center
David Klinkebiel, University of Nebraska Medical Center
Staci L. Peters, University of Nebraska Medical Center
Juraj Bies, National Cancer Institute, NIH
Jay Hannah, University of Nebraska at Omaha
Javeed Iqbal, University of Nebraska Medical Center
Kristi M. Anderson, University of Nebraska Medical Center
Hollie M. Siebler, University of Nebraska Medical Center
Lynette M. Smith, University of Nebraska Medical Center
Timothy C. Greiner, University of Nebraska Medical Center
Dhundy Bastola, University of Nebraska at OmahaFollow
Shantaram Joshi, University of Nebraska Medical Center
Oksana Lockridge, University of Nebraska Medical Center
Melanie A. Simpson, University of Nebraska - Lincoln
Dean W. Felsher, Stanford University
Kay-Uwe Wagner, University of Nebraska Medical Center
Wing C. Chan, University of Nebraska Medical Center
Judith K. Christman, University of Nebraska Medical Center
Rene Opavsky, University of Nebraska Medical Center

Author ORCID Identifier

Dhundy Bastola

Document Type

Article

Publication Date

1-2012

Publication Title

The Journal of Clinical Investigation

Volume

122

Issue

1

First Page

163

Last Page

177

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.

Comments

DOI: 10.1172/JCI57292

Recommended Citation

Hlady, Ryan A.; Novakova, Slavomira; Opavska, Jana; Klinkebiel, David; Peters, Staci L.; Bies, Juraj; Hannah, Jay; Iqbal, Javeed; Anderson, Kristi M.; Siebler, Hollie M.; Smith, Lynette M.; Greiner, Timothy C.; Bastola, Dhundy; Joshi, Shantaram; Lockridge, Oksana; Simpson, Melanie A.; Felsher, Dean W.; Wagner, Kay-Uwe; Chan, Wing C.; Christman, Judith K.; and Opavsky, Rene, "Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis" (2012). Interdisciplinary Informatics Faculty Publications. 58.
https://digitalcommons.unomaha.edu/interdiscipinformaticsfacpub/58