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

Oncotarget. 2016 Mar 15;7(11):12633-50. doi: 10.18632/oncotarget.7279.


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.

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

MeSH terms

  • Animals
  • Cell Transformation, Neoplastic / genetics*
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA Methylation
  • Humans
  • Mice
  • Mice, Knockout
  • Multiple Endocrine Neoplasia Type 1 / genetics
  • Multiple Endocrine Neoplasia Type 1 / metabolism*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*


  • MEN1 protein, human
  • Men1 protein, mouse
  • Proto-Oncogene Proteins
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNMT1 protein, human
  • Dnmt1 protein, mouse