TGF-β-Upregulated Acts as a Reservoir of miR-181 and Mediates Assembly of a Glycolytic Complex.

Long non-coding RNAs (lncRNAs) have emerged as key regulators in a wide range of biological processes. Here, we identified a mouse miRNA-host gene lncRNA () upregulated early during epithelial-to-mesenchymal transition (EMT). We show that when lncRNA is processed, it gives rise to two abundant polyadenylated isoforms, and , and a longer non-polyadenylated microprocessor-driven lnc-pri-miRNA containing clustered pre-miR-181a2 and pre-miR-181b2 hairpins. Ectopic expression of the or isoform enhanced cell migration and the invasive capacity of the cells, whereas the expression of the isoforms and miR-181a2 and miR-181b2 conferred anoikis resistance. gene deletion resulted in cells with lower adhesion capacity and reduced glycolytic metabolism, which are restored by isoform expression. We performed identification of direct RNA interacting proteins (iDRIP) to identify proteins interacting directly with the isoform. We defined a network of interacting proteins, including glycolytic enzymes, desmosome proteins and chaperone proteins; and we demonstrated that the isoform directly binds and acts as a scaffold molecule for the assembly of ENO1, ALDOA, GAPDH, and PKM glycolytic enzymes, along with LDHA, supporting substrate channeling for efficient glycolysis. Our results unveil a role of as a multifunctional lncRNA acting as a backbone for multiprotein complex formation and primary microRNAs.