Oncotarget

Research Papers:

Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Ziqiang Yuan, Carmen Sánchez Claros, Masako Suzuki, Elaine C. Maggi, Justin D. Kaner, Noah Kinstlinger, Jolanta Gorecka, Thomas J. Quinn, Rula Geha, Amanda Corn, Jessica Pastoriza, Qiang Jing, Asha Adem, Hao Wu, Girum Alemu, Yi-Chieh Du, Deyou Zheng, John M. Greally and Steven K. Libutti _

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Oncotarget. 2016; 7:12633-12650. https://doi.org/10.18632/oncotarget.7279

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Abstract

Ziqiang Yuan1, Carmen Sánchez Claros1, Masako Suzuki2, Elaine C. Maggi1, Justin D. Kaner3, Noah Kinstlinger1, Jolanta Gorecka1, Thomas J. Quinn1, Rula Geha1, Amanda Corn1, Jessica Pastoriza1, Qiang Jing2, Asha Adem1, Hao Wu1, Girum Alemu1, Yi-Chieh Du4, Deyou Zheng2,5,6, John M. Greally2,3,7, Steven K. Libutti1,2

1Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA

2Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA

3Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

4Department of Pathology and Lab Medicine, Weill Cornell Medical College, New York, New York, USA

5Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA

6Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA

7Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA

*These authors contributed equally to this work

Correspondence to:

Steven K. Libutti, e-mail: [email protected]

Keywords: MEN1, global DNA methylation, HELP-tagging, DNMT1, Sox/Wnt/β-catenin signaling pathway

Received: October 12, 2015     Accepted: January 24, 2016     Published: February 09, 2016

ABSTRACT

Multiple endocrine neoplasia type 1 (MEN1) syndrome results from mutations in the MEN1 gene and causes tumor formation via largely unknown mechanisms. Using a novel genome-wide methylation analysis, we studied tissues from MEN1-parathyroid tumors, Men1 knockout (KO) mice, and Men1 null mouse embryonic fibroblast (MEF) cell lines. We demonstrated that inactivation of menin (the protein product of MEN1) increases activity of DNA (cytosine-5)-methyltransferase 1 (DNMT1) by activating retinoblastoma-binding protein 5 (Rbbp5). The increased activity of DNMT1 mediates global DNA hypermethylation, which results in aberrant activation of the Wnt/β-catenin signaling pathway through inactivation of Sox regulatory genes. Our study provides important insights into the role of menin in DNA methylation and its impact on the pathogenesis of MEN1 tumor development.


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