title: Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors.
abstract: Biallelic inactivation of MEN1 encoding menin in pancreatic neuroendocrine tumors (PNETs) associated with the multiple endocrine neoplasia type 1 (MEN1) syndrome is well established, but how menin loss/inactivation initiates tumorigenesis is not well understood. We show that menin activates the long noncoding RNA maternally expressed gene 3 (Meg3) by histone-H3 lysine-4 trimethylation and CpG hypomethylation at the Meg3 promoter CRE site, to allow binding of the transcription factor cAMP response element-binding protein. We found that Meg3 has tumor-suppressor activity in PNET cells because the overexpression of Meg3 in MIN6 cells (insulin-secreting mouse PNET cell line) blocked cell proliferation and delayed cell cycle progression. Gene expression microarray analysis showed that Meg3 overexpression in MIN6 mouse insulinoma cells down-regulated the expression of the protooncogene c-Met (hepatocyte growth factor receptor), and these cells showed significantly reduced cell migration/invasion. Compared with normal islets, mouse or human MEN1-associated PNETs expressed less MEG3 and more c-MET. Therefore, a tumor-suppressor long noncoding RNA (MEG3) and suppressed protooncogene (c-MET) combination could elicit menin's tumor-suppressor activity. Interestingly, MEG3 and c-MET expression was also altered in human sporadic insulinomas (insulin secreting PNETs) with hypermethylation at the MEG3 promoter CRE-site coinciding with reduced MEG3 expression. These data provide insights into the β-cell proliferation mechanisms that could retain their functional status. Furthermore, in MIN6 mouse insulinoma cells, DNA-demethylating drugs blocked cell proliferation and activated Meg3 expression. Our data suggest that the epigenetic activation of lncRNA MEG3 and/or inactivation of c-MET could be therapeutic for treating PNETs and insulinomas.
authors.affiliation: Metabolic Diseases Branch (S.D.M., V.I.P., S.K.A.), National Institute of Diabetes and Digestive and Kidney Diseases, and Endocrine Oncology Branch (E.K.), National Cancer Institute, National Institutes of Health, Bethesda Maryland 20892.
authors.forename: Sita D
authors.initials: SD
authors.lastname: Modali
authors.forename: Vaishali I
authors.initials: VI
authors.lastname: Parekh
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.forename: Sunita K
authors.initials: SK
authors.lastname: Agarwal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007340:Insulinoma / Q000235:genetics / Q000473:pathology; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C498907:MEG3 non-coding RNA, human; C422882:MEG3 non-coding RNA, mouse; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D062085:RNA, Long Noncoding; D019859:Proto-Oncogene Proteins c-met