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

Ziqiang Yuan, Carmen Sánchez Claros, Masako Suzuki, Elaine C. Maggi, Justin D. Kaner, Noah Kinstlinger, Jolanta Gorecka, Thomas J. Quinn, Rula Geha, Amanda Corn, Jessica Pastoriza, Qiang Jing, Asha Adem, Hao Wu, Girum Alemu, Yi Chieh Du, Deyou Zheng, John M. Greally, Steven K. Libutti

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)12633-12650
Number of pages18
JournalOncotarget
Volume7
Issue number11
DOIs
StatePublished - Mar 15 2016

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Keywords

  • DNMT1
  • Global DNA methylation
  • HELP-tagging
  • MEN1
  • Sox/Wnt/β-catenin signaling pathway

ASJC Scopus subject areas

  • Oncology

Cite this

Yuan, Z., Claros, C. S., Suzuki, M., Maggi, E. C., Kaner, J. D., Kinstlinger, N., Gorecka, J., Quinn, T. J., Geha, R., Corn, A., Pastoriza, J., Jing, Q., Adem, A., Wu, H., Alemu, G., Du, Y. C., Zheng, D., Greally, J. M., & Libutti, S. K. (2016). Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis. Oncotarget, 7(11), 12633-12650. https://doi.org/10.18632/oncotarget.7279