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The lncRNA MEG3 is an epigenetic determinant of oncogenic signaling in multiple endocrine neoplasia type 1

Thursday, September 15, 2016 — Poster Session III

3:30 p.m. – 5:00 p.m.
FAES Terrace
NIDDK
MOLBIO-26

Authors

  • S Iyer
  • SK Agarwal

Abstract

Loss of tumor suppressors and gain of oncogenic properties is a hallmark of cancer. But the pathways leading to tumor formation are poorly understood. One such tumor syndrome, the multiple endocrine neoplasia type 1 (MEN1), exhibits germline mutations in the MEN1 gene and tissue-specific loss of the encoded tumor suppressor protein menin. Consequently, tumors develop in multiple endocrine organs – the pancreatic islets, the pituitary and, the parathyroid. Insulinomas are the most common type of functioning pancreatic neuroendocrine tumors (PNETs). Previous studies revealed that menin loss downregulated the Maternally Expressed Gene 3 (MEG3) by promoter hypermethylation. MEG3 is transcribed into a long-non-coding RNA (LnCRNA) mapping to the imprinted DLK1-MEG3 locus on human chromosome 14q32.3. Gene expression microarray analyses, of mouse insulinoma MIN6 cells stably transfected with Meg3 showed a five–fold decrease in proto-oncogenic signaling factor c-Met, suggesting a tumor suppressor function for Meg3. We documented MEG3 downregulation with concurrent upregulation of c-MET in endocrine tumors, but the molecular basis remains elusive. Our work identifies putative mechanisms by which MEG3 inhibits oncogenic c-MET signaling to suppress tumorigenesis. We provide direct evidence for the first time that ectopically expressed Meg3 isoforms can attenuate the highly abundant c-MET transcript in MIN6 insulinoma cells. Meg3 interacts with the epigenetic machinery, such as the Polycomb Repressive Complex 2 (PRC2) to regulate c-Met. Additionally, mutational analyses pinpoint the region of Meg3 responsible for mediating c-Met repression. Thus, our study supports the conclusion that Meg3 is an important determinant of oncogenic signaling in MEN1-associated endocrine tumors.

Category: Molecular Biology and Biochemistry