Journal Article

Regulation of miR-483-3p by the O-linked N-acetylglucosamine transferase links chemosensitivity to glucose metabolism in liver cancer cells

Lanuti, P, Visone, R, Rossi, C, Mariani-Costantini, R, Veronese, A, Pepe, F, Soliman, S, Braconi, C, Pagotto, S

2017

Overview

The miR-483-3p is upregulated in several tumors, including liver tumors, where it inhibits TP53-dependent apoptosis by targeting the pro-apoptotic gene BBC3 /PUMA. The transcriptional regulation of the miR-483-3p could be driven by the β-catenin/USF1 complex, independently from its host gene IGF2, and we previously demonstrated that in HepG2 hepatoblastoma cells carrying wild-type TP53 the upregulation of the miR-483-3p overcomes the antitumoral effects of the tumor-suppressor miR-145-5p by a mechanism involving cellular glucose availability. Here we demonstrate that in HepG2 cells, the molecular link between glucose concentration and miR-483-3p expression entails the O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which stabilizes the transcriptional complex at the miR-483 promoter. HepG2 cells showed reduced miR-483-3p expression and increased susceptibility to 5-fluorouracil (5-FU)-induced apoptosis in presence of the inhibitor of glycolysis 2-deoxy- d -glucose (2-DG). However, i n vivo experiments showed that HepG2 cells with higher miR-483-3p expression were selected during tumor progression regardless of 5-FU treatment. Furthermore, treatment with 2-DG alone did not significantly reduce HepG2 xenograft load in immunodeficient mice. In conclusion, we show that in HepG2 cells glucose uptake increases the expression of the oncogenic miR-483-3p through the OGT pathway. This suggests that depletion of the miR-483-3p may be a valuable therapeutic approach in liver cancer patients, but the use of inhibitors of glycolysis to achieve this purpose could accelerate the selection of resistant neoplastic cell clones.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/109 / 13/2 / 13/89 / 38/22 / 38/77 / 45/15 / 5-Fluorouracil / 631/67/1059/2326 / 631/67/2327 / 64/60 / 82/29 / Apoptosis / Cell Biology / Gene regulation / Glucose / Glucose metabolism / Glycolysis / Hepatocytes / Human Genetics / Immunodeficiency / Insulin-like growth factor II / Internal Medicine / Liver cancer / Medicine / Medicine & Public Health / Metabolism / N-Acetylglucosamine / Oncology / Original / original-article / p53 Protein / Transcription / Tumors / Xenografts / β-catenin