title: Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis.
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.
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sánchez Claros
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Masako
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Maggi
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Justin D
authors.initials: JD
authors.lastname: Kaner
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Kinstlinger
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Gorecka
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Quinn
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Rula
authors.initials: R
authors.lastname: Geha
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Corn
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Pastoriza
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Jing
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Asha
authors.initials: A
authors.lastname: Adem
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Girum
authors.initials: G
authors.lastname: Alemu
authors.affiliation: Department of Pathology and Lab Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Du
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Greally
authors.affiliation: Department of Surgery, Albert Einstein College of Medicine, Bronx, New York, USA.|Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Libutti
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism*; D019175:DNA Methylation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse
keywords: DNMT1; HELP-tagging; MEN1; Sox/Wnt/β-catenin signaling pathway; global DNA methylation