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.
Highlights
Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by tumors of the endocrine glands, including the parathyroid, anterior pituitary, and endocrine pancreas
By LUminometric Methylation Assay (LUMA), that levels of global DNA methylation were significantly decreased in the Men1 null cells following 5-aza-2ʹ-deoxycytidine treatment compared to the Men1 null cells without 5-aza-2ʹdeoxycytidine treatment (Figure 11B)
The characterization of global DNA methylation patterns in the genomes of tissues with loss of the MEN1 tumor suppressor gene appeared an attractive area of investigation
Summary
Multiple endocrine neoplasia type 1 (MEN1) is a familial cancer syndrome characterized by tumors of the endocrine glands, including the parathyroid, anterior pituitary, and endocrine pancreas. Somatic mutations in MEN1 are frequently identified in sporadic parathyroid adenomas, insulinomas, gastrinomas, non-functional pancreatic neuroendocrine tumors, and lung carcinoids [1,2,3,4,5]. Epigenetic alterations are important in tumorigenesis and include histone post-transcriptional modifications, direct DNA methylation, chromatin organization, and non-coding regulatory RNA [17]. Inactivation of menin was found to reduce binding to protein arginine N-methyltransferase 5 (PRMT5), decreasing Gas expression in MEN1 tumors [23]. Frequent DNA hypermethylation of cyclin-dependent kinase inhibitor 2A (CDKN2A), Ras association domain family member 1 (RASSF1A), and adenomatous polyposis coli (APC)
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