title: Menin and Daxx Interact to Suppress Neuroendocrine Tumors through Epigenetic Control of the Membrane Metallo-Endopeptidase.
abstract: Neuroendocrine tumors (NET) often harbor loss-of-function mutations in the MEN1 and DAXX tumor suppressor genes. Here, we report that the products of these genes, menin and Daxx, interact directly with each other to suppress the proliferation of NET cells, to a large degree by inhibiting expression of the membrane metallo-endopeptidase (MME). Menin and Daxx were required to enhance histone H3 lysine9 trimethylation (H3K9me3) at the MME promoter, as mediated partly by the histone H3 methyltransferase SUV39H1. Notably, the menin T429K mutation associated with a NET syndrome reduced Daxx binding, MME repression, and proliferation of NET cells. Conversely, inhibition of MME in NET cells repressed proliferation and tumor growth in vivo Our findings reveal a previously unappreciated cross-talk between two crucial tumor suppressor genes thought to work by independent pathways, focusing on MME as a common target of menin/Daxx to treat NET. Cancer Res; 77(2); 401-11. ©2016 AACR.
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.|Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Zijie
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.
authors.forename: Zongzhe
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Biochemistry and Biophysics, AFCRI, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: John
authors.initials: J
authors.lastname: Domsic
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Endocrinology and Metabolism, the First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Chiying
authors.initials: C
authors.lastname: An
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.
authors.forename: Bowen
authors.initials: B
authors.lastname: Xing
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Xiuheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David C
authors.initials: DC
authors.lastname: Metz
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.|Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yang
authors.affiliation: Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.|Department of Biochemistry and Biophysics, AFCRI, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.affiliation: Shenzhen University College of Medicine, Medical Center and Diabetes Center, Shenzhen, China. huax@mail.med.upenn.edu xsm@szu.edu.cn.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Cancer Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. huax@mail.med.upenn.edu xsm@szu.edu.cn.|Abramson Family Cancer Research Institute (AFCRI), Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D056970:Co-Repressor Proteins; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones; D015260:Neprilysin / Q000096:biosynthesis / Q000235:genetics*; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C105373:MEN1 protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015260:Neprilysin