Repression of microRNA-768-3p by MEK/ERK signalling contributes to enhanced mRNA translation in human melanoma

• Published in: Oncogene Vol. 33; no. 20; pp. 2577 - 2588
• Main Authors: Jiang, C C, Croft, A, Tseng, H-Y, Guo, S T, Jin, L, Hersey, P, Zhang, X D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.05.2014; Nature Publishing Group
• Subjects: 3' Untranslated regions; 631/337/384/331; 631/337/574; 631/80/86; 692/699/67/1813/1634; Apoptosis; Cell Biology; Cell Line, Tumor; Cell survival; Down-Regulation; Eukaryotic Initiation Factor-4E - metabolism; Extracellular signal-regulated kinase; Genetic aspects; Genetic translation; Human Genetics; Humans; Initiation factor eIF-4E; Internal Medicine; Kinases; Malignancy; MAP kinase; MAP Kinase Signaling System; Medicine; Medicine & Public Health; MEK inhibitors; Melanocytes; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Metabolic pathways; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Mitogen-activated protein kinases; mRNA; Oncology; original-article; Phosphorylation; Physiological aspects; Protein Biosynthesis; Protein expression; Protein kinase; Protein synthesis; Proteins; RNA, Messenger - genetics; Signal Transduction; Up-Regulation; RAF/MEK/ERK; melanoma; eIF4E; mRNA translation; miR-768-3p
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2013.237

Increased global protein synthesis and selective translation of mRNAs encoding proteins contributing to malignancy is common in cancer cells. This is often associated with elevated expression of eukaryotic translation initiation factor 4 (eIF4E), the rate-limiting factor of cap-dependent translation initiation. We report here that in human melanoma downregulation of miR-768-3p as a result of activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway has an important role in the upregulation of eIF4E and enhancement in protein synthesis. Melanoma cells displayed increased nascent protein production and elevated eIF4E expression, which was associated with the downregulation of miR-768-3p that was predicted to target the 3′-untranslated region of the eIF4E mRNA. Overexpression of miR-768-3p led to the downregulation of the endogenous eIF4E protein, reduction in nascent protein synthesis and inhibition of cell survival and proliferation. These effects were efficiently reversed when eIF4E was co-overexpressed in melanoma cells. On the other hand, introduction of anti-miR-768-3p into melanocytes upregulated endogenous eIF4E protein expression and increased global protein synthesis. Downregulation of miR-768-3p appeared to be mediated by activation of the MEK/ERK pathway, in that treatment of BRAF V600E melanoma cells with the mutant BRAF inhibitor PLX4720 or exposure of either BRAF V600E or wild-type BRAF melanoma cells to the MEK inhibitor U0126 resulted in the upregulation of miR-768-3p and inhibition of nascent protein synthesis. This inhibition was partially blocked in cells cointroduced with anti-miR-768-3p. Significantly, miR-768-3p was similarly downregulated, which was inversely associated with the expression levels of eIF4E in fresh melanoma isolates. Taken together, these results identify downregulation of miR-768-3p and subsequent upregulation of eIF4E as an important mechanism in addition to phosphorylation of eIF4E responsible for MEK/ERK-mediated enhancement of protein synthesis in melanoma.