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The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

ABSTRACT: The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impaired insulin signaling and decreased glucose uptake. Furthermore, acute hyperinsulinemia downregulates H19, a phenomenon that occurs through PI3K/AKT-dependent phosphorylation of the miRNA processing factor KSRP, which promotes biogenesis of let-7 and its mediated H19 destabilization. Our results reveal a previously undescribed double-negative feedback loop between sponge lncRNA and target miRNA that contributes to glucose regulation in muscle cells.

SUBMITTER: Gao Y

PROVIDER: S-EPMC4267628 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

Gao Yuan Y Wu Fuju F Zhou Jichun J Yan Lei L Jurczak Michael J MJ Lee Hui-Young HY Yang Lihua L Mueller Martin M Zhou Xiao-Bo XB Dandolo Luisa L Szendroedi Julia J Roden Michael M Flannery Clare C Taylor Hugh H Carmichael Gordon G GG Shulman Gerald I GI Huang Yingqun Y

Nucleic acids research 20141115 22

The H19 lncRNA has been implicated in development and growth control and is associated with human genetic disorders and cancer. Acting as a molecular sponge, H19 inhibits microRNA (miRNA) let-7. Here we report that H19 is significantly decreased in muscle of human subjects with type-2 diabetes and insulin resistant rodents. This decrease leads to increased bioavailability of let-7, causing diminished expression of let-7 targets, which is recapitulated in vitro where H19 depletion results in impa ...[more]

PMID: 25399420

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Project description:Epithelial-mesenchymal transition (EMT) is an important biological process that has been implicated in cancer metastasis. Epithelial cell adhesion molecule (EpCAM) is expressed at the basolateral membrane of most normal epithelial cells but is overexpressed in many epithelial cancers. In our studies on the role of EpCAM in cancer biology, we observed that EpCAM expression is decreased in mesenchymal-like primary cancer specimens in vivo and following induction of EMT in cancer cell lines in vitro. Extracellular signal-related kinase (ERK) is a key regulator of EMT. We observed that EpCAM expression is decreased with activation of the ERK pathway in primary cancer specimens in vivo and in cancer cell lines in vitro. In experimental models, growth factor stimulation and/or oncogene-induced ERK2 activation suppressed EpCAM expression, whereas genetic or pharmacological inhibition of the ERK pathway restored EpCAM expression. In detailed studies of the EpCAM promoter region, we observed that ERK2 suppresses EpCAM transcription directly by binding to a consensus ERK2-binding site in the EpCAM promoter and indirectly through activation of EMT-associated transcription factors SNAI1, SNAI2, TWIST1 and ZEB1, which bind to E-box sites in the EpCAM promoter. Surprisingly, EpCAM appears to modulate ERK activity. Using multiple cell lines, we demonstrated that specific ablation of EpCAM resulted in increased ERK pathway activity and SNAI2 expression, migration and invasion, whereas forced expression of EpCAM resulted in decreased ERK pathway activity and SNAI2 expression, migration and invasion. These observations provide important insights into the regulation of EpCAM expression during EMT, demonstrate an unexpected role for EpCAM in the regulation of ERK and define a novel double-negative feedback loop between EpCAM and ERK that contributes to the regulation of EMT. These studies have important translational implications as both EpCAM and ERK are currently being targeted in human clinical trials.

Dataset Information

The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

Publications

The H19/let-7 double-negative feedback loop contributes to glucose metabolism in muscle cells.

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