PMID- 25565142
OWN - NLM
STAT- MEDLINE
DCOM- 20160229
LR  - 20181113
IS  - 1944-9917 (Electronic)
IS  - 0888-8809 (Print)
IS  - 0888-8809 (Linking)
VI  - 29
IP  - 2
DP  - 2015 Feb
TI  - Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic 
      neuroendocrine tumors.
PG  - 224-37
LID - 10.1210/me.2014-1304 [doi]
AB  - 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 beta-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.
FAU - Modali, Sita D
AU  - Modali SD
AD  - 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.
FAU - Parekh, Vaishali I
AU  - Parekh VI
FAU - Kebebew, Electron
AU  - Kebebew E
FAU - Agarwal, Sunita K
AU  - Agarwal SK
LA  - eng
PT  - Journal Article
DEP - 20150107
PL  - United States
TA  - Mol Endocrinol
JT  - Molecular endocrinology (Baltimore, Md.)
JID - 8801431
RN  - 0 (MEG3 non-coding RNA, human)
RN  - 0 (MEG3 non-coding RNA, mouse)
RN  - 0 (Men1 protein, mouse)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Long Noncoding)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Cell Movement/genetics
MH  - Cell Proliferation
MH  - DNA Methylation
MH  - *Epigenesis, Genetic
MH  - *Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Insulinoma/genetics/pathology
MH  - Islets of Langerhans/metabolism/pathology
MH  - Mice
MH  - Neuroendocrine Tumors/*genetics/pathology
MH  - Pancreatic Neoplasms/*genetics/pathology
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-met/*genetics/metabolism
MH  - RNA, Long Noncoding/*genetics/metabolism
MH  - Up-Regulation
PMC - PMC4318878
EDAT- 2015/01/08 06:00
MHDA- 2016/03/02 06:00
PMCR- 2016/02/01
CRDT- 2015/01/08 06:00
PHST- 2015/01/08 06:00 [entrez]
PHST- 2015/01/08 06:00 [pubmed]
PHST- 2016/03/02 06:00 [medline]
PHST- 2016/02/01 00:00 [pmc-release]
AID - me-14-1304 [pii]
AID - 10.1210/me.2014-1304 [doi]
PST - ppublish
SO  - Mol Endocrinol. 2015 Feb;29(2):224-37. doi: 10.1210/me.2014-1304. Epub 2015 Jan 
      7.