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

doi:10.18632/oncotarget.7279

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 journal › Article › peer-review

19 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 language	English (US)
Pages (from-to)	12633-12650
Number of pages	18
Journal	Oncotarget
Volume	7
Issue number	11
DOIs	https://doi.org/10.18632/oncotarget.7279
State	Published - Mar 15 2016

Keywords

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

ASJC Scopus subject areas

Oncology

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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

Yuan, Z, Claros, CS, 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, YC, Zheng, D , Greally, JM & Libutti, SK 2016, 'Loss of MEN1 activates DNMT1 implicating DNA hypermethylation as a driver of MEN1 tumorigenesis', Oncotarget, vol. 7, no. 11, pp. 12633-12650. https://doi.org/10.18632/oncotarget.7279

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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.",

keywords = "DNMT1, Global DNA methylation, HELP-tagging, MEN1, Sox/Wnt/β-catenin signaling pathway",

author = "Ziqiang Yuan and Claros, {Carmen S{\'a}nchez} and Masako Suzuki and Maggi, {Elaine C.} and Kaner, {Justin D.} and Noah Kinstlinger and Jolanta Gorecka and Quinn, {Thomas J.} and Rula Geha and Amanda Corn and Jessica Pastoriza and Qiang Jing and Asha Adem and Hao Wu and Girum Alemu and Du, {Yi Chieh} and Deyou Zheng and Greally, {John M.} and Libutti, {Steven K.}",

note = "Funding Information: This work was supported in part by the NCI (R01-CA170911), the Albert Einstein College of Medicine, and a generous gift from Linda and Earle Altman. We thank Dr. Sunita K. Agarwal for providing the mouse Men1 null cell line and menin plasmids, and Dr. Allen Spiegel for useful discussion and suggestions.",

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AU - Yuan, Ziqiang

AU - Claros, Carmen Sánchez

AU - Suzuki, Masako

AU - Maggi, Elaine C.

AU - Kaner, Justin D.

AU - Kinstlinger, Noah

AU - Gorecka, Jolanta

AU - Quinn, Thomas J.

AU - Geha, Rula

AU - Corn, Amanda

AU - Pastoriza, Jessica

AU - Jing, Qiang

AU - Adem, Asha

AU - Wu, Hao

AU - Alemu, Girum

AU - Du, Yi Chieh

AU - Zheng, Deyou

AU - Greally, John M.

AU - Libutti, Steven K.

N1 - Funding Information: This work was supported in part by the NCI (R01-CA170911), the Albert Einstein College of Medicine, and a generous gift from Linda and Earle Altman. We thank Dr. Sunita K. Agarwal for providing the mouse Men1 null cell line and menin plasmids, and Dr. Allen Spiegel for useful discussion and suggestions.

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

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

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Keywords

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