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.