Project title: Elucidate the role of the MEN1 gene in carcinoid tumors and determine a functional connection between the genes MEN1, Rbp2 and p27

Matthew Meyerson, MD, PhD Dana-Farber Cancer Institute

Matthew Meyerson, MD, PhD
  • Status: Completed
  • Year(s): 2006
  • Research Type: Basic
  • Primary Site: Small intestine
  • Area of Inquiry: Mapping NET dependencies

General Description

The most common known mutation in human neuroendocrine tumors is in the MEN1 gene. Dr. Meyerson’s laboratory has uncovered a biochemical function for the menin protein produced by this gene. Menin modifies the structure of histone proteins that are bound to DNA. The goal of this project is to map the specific modifications made to the histone proteins and also to look for enzymes whose action counteracts the activity of menin. Since menin function is absent in carcinoid tumors, inhibiting enzymes with opposite activity may be useful for carcinoid treatment.  Researchers hope to elucidate the role of the MEN1 gene in carcinoid tumors and to determine a functional connection between the genes MEN1, Rbp2 and p27.

Results

Meyerson found that MEN1 helps to add an important protein modification (called histone methylation) that controls gene expression, and that MEN1 mutations impair this addition. Based on this discovery, Meyerson hypothesized that it might be possible to partly offset the effects of MEN1 mutations by inhibiting another gene, called RBP2, which removes this same protein modification. In other words, inhibiting RBP2 might help restore the appropriate balance. Remarkably, he found that this approach works: mice carrying mutations in both MEN1 and RBP2 survive much longer than mice carrying only MEN1 mutations.

In July 2011, published results suggest a novel strategy for treating neuroendocrine tumors without menin function (as well as other cancer types) by inhibiting a specific class of enzymes, histone H3 trimethyl-lysine 4 demethylase enzymes. Dr. William Kaelin, a colleague of Dr. Meyerson, identified the first histone H3 trimethyl-lysine 4 demethylase; RBP2. Dr. Meyerson’s team has shown that Rbp2 inhibition can slow tumorigenesis caused by loss of menin function in mice with neuroendocrine tumors. This work suggests that RBP2 inhibitors should be developed and might have anti-cancer effects in patients with neuroendocrine cancers. 

Publications

Francis J, Lin W, Rozenblatt-Rosen O, Meyerson M. The menin tumor suppressor protein is phosphorylated in response to DNA damage. PLoS One. 2011 Jan 14;6(1):e16119. doi: 10.1371/journal.pone.0016119.

1: Agarwal SK. The future: genetics advances in MEN1 therapeutic approaches and management strategies. Endocr Relat Cancer. 2017 Oct;24(10):T119-T134. doi: 10.1530/ERC-17-0199. Review. PubMed PMID: 28899949; PubMed Central PMCID: PMC5679100.

2: Feng Z, Ma J, Hua X. Epigenetic regulation by the menin pathway. Endocr Relat Cancer. 2017 Oct;24(10):T147-T159. doi: 10.1530/ERC-17-0298. Epub 2017 Aug 15. Review. PubMed PMID: 28811300; PubMed Central PMCID: PMC5612327.

3: Yuan Z, Sánchez Claros C, 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. 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. PubMed PMID: 26871472; PubMed Central PMCID: PMC4914310.

4: Agarwal SK. Exploring the tumors of multiple endocrine neoplasia type 1 in mouse models for basic and preclinical studies. Int J Endocr Oncol. 2014;1(2):153-161. PubMed PMID: 25685317; PubMed Central PMCID: PMC4327775.

5: Cierpicki T, Grembecka J. Challenges and opportunities in targeting the menin-MLL interaction. Future Med Chem. 2014 Mar;6(4):447-62. doi: 10.4155/fmc.13.214. Review. PubMed PMID: 24635524; PubMed Central PMCID: PMC4138051.

6: Chang CW, Chen CR, Huang CY, Shu WY, Chiang CS, Hong JH, Hsu IC. Comparative transcriptome profiling of an SV40-transformed human fibroblast (MRC5CVI) and its untransformed counterpart (MRC-5) in response to UVB irradiation. PLoS One. 2013 Sep 3;8(9):e73311. doi: 10.1371/journal.pone.0073311. eCollection 2013. PubMed PMID: 24019915; PubMed Central PMCID: PMC3760899.

7: Matkar S, Thiel A, Hua X. Menin: a scaffold protein that controls gene expression and cell signaling. Trends Biochem Sci. 2013 Aug;38(8):394-402. doi: 10.1016/j.tibs.2013.05.005. Epub 2013 Jul 10. Review. PubMed PMID: 23850066; PubMed Central PMCID: PMC3741089.

8: Agarwal SK. Multiple endocrine neoplasia type 1. Front Horm Res. 2013;41:1-15. doi: 10.1159/000345666. Epub 2013 Mar 19. Review. PubMed PMID: 23652667; PubMed Central PMCID: PMC6281166.

9: Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N, Green MR. MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Mol Cell Biol. 2013 Jul;33(13):2635-47. doi: 10.1128/MCB.00167-13. Epub 2013 May 6. PubMed PMID: 23648481; PubMed Central PMCID: PMC3700119.

10: Yang YJ, Song TY, Park J, Lee J, Lim J, Jang H, Kim YN, Yang JH, Song Y, Choi A, Lee HY, Jo CH, Han JW, Kim ST, Youn HD, Cho EJ. Menin mediates epigenetic regulation via histone H3 lysine 9 methylation. Cell Death Dis. 2013 Apr 11;4:e583. doi: 10.1038/cddis.2013.98. PubMed PMID: 23579270; PubMed Central PMCID: PMC3668625.

11: Feng ZJ, Gurung B, Jin GH, Yang XL, Hua XX. SUMO modification of menin. Am J Cancer Res. 2013;3(1):96-106. Epub 2013 Jan 18. PubMed PMID: 23359867; PubMed Central PMCID: PMC3555195.

12: Ren F, Xu HW, Hu Y, Yan SH, Wang F, Su BW, Zhao Q. Expression and subcellular localization of menin in human cancer cells. Exp Ther Med. 2012 Jun;3(6):1087-1091. Epub 2012 Mar 29. PubMed PMID: 22970022; PubMed Central PMCID: PMC3438647.

Lin W, Cao J, Liu J, Beshiri ML, Fujiwara Y, Francis J, Cherniack AD, Geisen C, Blair LP, Zou MR, Shen X, Kawamori D, Liu Z, Grisanzio C, Watanabe H, Minamishima YA, Zhang Q, Kulkarni RN, Signoretti S, Rodig SJ, Bronson RT, Orkin SH, Tuck DP, Benevolenskaya, EV, Meyerson M, Kaelin WG, Yan Q. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proceedings of the National Academy of Sciences Aug 2011, 108 (33) 13379-13386; DOI:10.1073/pnas.1110104108.

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Additional Details

  • Grant Duration: 2 years
  • Awards: No information
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