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

TitleLoss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsYuan Z, Claros CSánchez, Suzuki M, Maggi EC, Kaner JD, Kinstlinger N, Gorecka J, Quinn TJ, Geha R, Corn A, Pastoriza J, Jing Q, Adem A, Wu H, Alemu G, Du Y-C, Zheng D, Greally JM, Libutti SK
JournalOncotarget
Volume7
Issue11
Pagination12633-50
Date Published2016 Mar 15
ISSN1949-2553
KeywordsAnimals, Cell Transformation, Neoplastic, DNA (Cytosine-5-)-Methyltransferase 1, DNA Methylation, Humans, Mice, Mice, Knockout, Multiple Endocrine Neoplasia Type 1, Proto-Oncogene Proteins
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.

DOI10.18632/oncotarget.7279
Alternate JournalOncotarget
PubMed ID26871472
PubMed Central IDPMC4914310
Grant ListP30 DK041296 / DK / NIDDK NIH HHS / United States
P50 CA174521 / CA / NCI NIH HHS / United States
R01 CA170911 / CA / NCI NIH HHS / United States

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