Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c.
Menin, the product of the Men1 gene mutated in familial multiple endocrine neoplasia type 1 (MEN1), regulates transcription in differentiated cells. Menin associates with and modulates the histone methyltransferase activity of a nuclear protein complex to activate gene expression. However, menin-dependent histone methyltransferase activity in endocrine cells has not been demonstrated, and the mechanism of endocrine tumor suppression by menin remains unclear. Here, we show that menin-dependent histone methylation maintains the in vivo expression of cyclin-dependent kinase (CDK) inhibitors to prevent pancreatic islet tumors. In vivo expression of CDK inhibitors, including p27 and p18, and other cell cycle regulators is disrupted in mouse islet tumors lacking menin. Chromatin immunoprecipitation studies reveal that menin directly associates with regions of the p27 and p18 promoters and increases methylation of lysine 4 (Lys-4) in histone H3 associated with these promoters. Moreover, H3 Lys-4 methylation associated with p27 and p18 is reduced in islet tumors from Men1 mutant mice. Thus, H3 Lys-4 methylation is a crucial function of menin in islet tumor suppression. These studies suggest an epigenetic mechanism of tumor suppression: by promoting histone modifications, menin maintains transcription at multiple loci encoding cell cycle regulators essential for endocrine growth control.
Karnik
Satyajit K
SK
Departments of Developmental Biology and Medicine (Oncology Division), Stanford University School of Medicine, Stanford, CA 94305-5329.
Hughes
Christina M
CM
Gu
Xueying
X
Rozenblatt-Rosen
Orit
O
McLean
Graeme W
GW
Xiong
Yue
Y
Meyerson
Matthew
M
Kim
Seung K
SK
D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000096:biosynthesis*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D007515:Islets of Langerhans / Q000254:growth & development* / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D018761:Multiple Endocrine Neoplasia Type 1 / Q000378:metabolism; D011496:Protein Methyltransferases; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D050763:Cyclin-Dependent Kinase Inhibitor p18; D006657:Histones; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008156:Luciferases; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase