PMID- 28811299 OWN - NLM STAT- MEDLINE DCOM- 20180508 LR - 20181113 IS - 1479-6821 (Electronic) IS - 1351-0088 (Print) IS - 1351-0088 (Linking) VI - 24 IP - 10 DP - 2017 Oct TI - Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. PG - T135-T145 LID - 10.1530/ERC-17-0281 [doi] AB - Since the discovery of the multiple endocrine neoplasia type 1 (MEN1) gene in 1997, elucidation of the molecular function of its protein product, menin, has been a challenge. Biochemical, proteomics, genetics and genomics approaches have identified various potential roles, which converge on gene expression regulation. The most consistent findings show that menin connects transcription factors and chromatin-modifying enzymes, in particular, the histone H3K4 methyltransferase complexes MLL1 and MLL2. Chromatin immunoprecipitation combined with next-generation sequencing has enabled studying genome-wide dynamics of chromatin binding by menin. We propose that menin regulates cell type-specific transcriptional programs by linking chromatin regulatory complexes to specific transcription factors. In this fashion, the MEN1 gene is a tumor suppressor gene in the endocrine tissues that are affected in MEN1. Recent studies have hinted at possibilities to pharmacologically restore the epigenetic changes caused by loss of menin function as therapeutic strategies for MEN1, for example, by inhibition of histone demethylases. The current lack of appropriate cellular model systems for MEN1-associated tumors is a limitation for compound testing, which needs to be addressed in the near future. In this review, we look back at the past twenty years of research on menin and the mechanism of disease of MEN1. In addition, we discuss how the current understanding of the molecular function of menin offers future directions to develop novel treatments for MEN1-associated endocrine tumors. CI - (c) 2017 Society for Endocrinology. FAU - Dreijerink, Koen M A AU - Dreijerink KMA AD - Department of EndocrinologyVU University Medical Center, Amsterdam, The Netherlands. FAU - Timmers, H T Marc AU - Timmers HTM AD - German Cancer Consortium (DKTK) partner site FreiburgGerman Cancer Research Center (DKFZ) and Department of Urology, Medical Center-University of Freiburg, Freiburg, Germany. FAU - Brown, Myles AU - Brown M AD - Department of Medical OncologyDana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA myles_brown@dfci.harvard.edu. LA - eng GR - P01 CA080111/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Review DEP - 20170815 PL - England TA - Endocr Relat Cancer JT - Endocrine-related cancer JID - 9436481 RN - 0 (MEN1 protein, human) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factors) SB - IM MH - Epigenesis, Genetic/*genetics MH - Humans MH - Multiple Endocrine Neoplasia Type 1/*genetics/metabolism MH - Neuroendocrine Tumors/*genetics/metabolism MH - Proto-Oncogene Proteins/*metabolism MH - Time Factors MH - Transcription Factors/*genetics PMC - PMC5609455 MID - NIHMS904605 OTO - NOTNLM OT - histone H3K4 trimethylation OT - menin OT - multiple endocrine neoplasia type 1 (MEN1) OT - transcriptional regulation COIS- Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. EDAT- 2017/08/16 06:00 MHDA- 2018/05/09 06:00 PMCR- 2018/10/01 CRDT- 2017/08/17 06:00 PHST- 2017/08/09 00:00 [received] PHST- 2017/08/14 00:00 [accepted] PHST- 2017/08/16 06:00 [pubmed] PHST- 2018/05/09 06:00 [medline] PHST- 2017/08/17 06:00 [entrez] PHST- 2018/10/01 00:00 [pmc-release] AID - ERC-17-0281 [pii] AID - 10.1530/ERC-17-0281 [doi] PST - ppublish SO - Endocr Relat Cancer. 2017 Oct;24(10):T135-T145. doi: 10.1530/ERC-17-0281. Epub 2017 Aug 15.