Loss of<i>MEN1</i>activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis

Abstract

// Ziqiang Yuan 1 , Carmen S&aacute;nchez Claros 1 , Masako Suzuki 2 , Elaine C. Maggi 1 , Justin D. Kaner 3 , Noah Kinstlinger 1 , Jolanta Gorecka 1 , Thomas J. Quinn 1 , Rula Geha 1 , Amanda Corn 1 , Jessica Pastoriza 1 , Qiang Jing 2 , Asha Adem 1 , Hao Wu 1 , Girum Alemu 1 , Yi-Chieh Du 4 , Deyou Zheng 2, 5, 6 , John M. Greally 2, 3, 7 , Steven K. Libutti 1, 2 1 Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA 2 Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA 3 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA 4 Department of Pathology and Lab Medicine, Weill Cornell Medical College, New York, New York, USA 5 Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA 6 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA 7 Department 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: slibutti@montefiore.org Keywords: MEN1, global DNA methylation, HELP-tagging, DNMT1, Sox/Wnt/&beta;-catenin signaling pathway Received: October 12, 2015&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: January 24, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; 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/&beta;-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.