Unknown

Dataset Information

0

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 ?-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.

SUBMITTER: Modali SD 

PROVIDER: S-EPMC4318878 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

Epigenetic regulation of the lncRNA MEG3 and its target c-MET in pancreatic neuroendocrine tumors.

Modali Sita D SD   Parekh Vaishali I VI   Kebebew Electron E   Agarwal Sunita K SK  

Molecular endocrinology (Baltimore, Md.) 20150107 2


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 respons  ...[more]

Similar Datasets

| S-EPMC10816436 | biostudies-literature
| S-EPMC9209739 | biostudies-literature
| S-EPMC7340809 | biostudies-literature
| S-EPMC5660463 | biostudies-literature
| S-EPMC5523063 | biostudies-literature
| S-EPMC8761900 | biostudies-literature
| S-EPMC4208619 | biostudies-literature
| S-EPMC7039111 | biostudies-literature
| S-EPMC3354652 | biostudies-literature
| S-EPMC5506272 | biostudies-literature