3 years ago

The Long Non-Coding RNA MEG3 is an Epigenetic Determinant of Oncogenic Signaling in Functional Pancreatic Neuroendocrine Tumor Cells.

Agarwal, Modali, Iyer
The long non-coding RNA (lncRNA) MEG3 is significantly downregulated in pancreatic neuroendocrine tumors (PNETs). MEG3 loss corresponds with aberrant upregulation of the oncogenic HGF receptor c-MET in PNETs. Meg3 overexpression, in a mouse insulin-secreting PNET cell line, MIN6, downregulates c-Met expression. However, the molecular mechanism by which MEG3 regulates c-MET is not known. Using chromatin isolation by RNA purification and sequencing (ChIRP-Seq), we identified Meg3 binding to unique genomic regions, in and around the c-Met gene. In the absence of Meg3, these c-Met regions displayed distinctive enhancer-signature histone modifications. Furthermore, Meg3 relied on functional EZH2, a component of the Polycomb Repressive Complex 2 (PRC2) to inhibit c-Met expression. Another mechanism of lncRNA-mediated regulation of gene expression utilized triplex forming GA-GT rich sequences. Transfection of such motifs from Meg3 RNA, termed triplex forming oligos (TFOs), in MIN6 cells, suppressed c-Met expression and enhanced cell proliferation, perhaps by modulating other targets. This study comprehensively establishes epigenetic mechanisms underlying Meg3 control of c-Met and the oncogenic consequences of Meg3 loss or c-Met gain. These findings have clinical relevance for targeting c-MET in PNETs. There is also the potential for pancreatic islet ß-cell expansion through c-MET regulation, to ameliorate ß-cell loss in diabetes.

Publisher URL: http://doi.org/10.1128/MCB.00278-17

DOI: 10.1128/MCB.00278-17

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