A Kahn

A Veronese

C Butkinaree

C Chen

C Livingstone

C Slawson

CC Huang

DJ Langford

E Cognard

E Varkonyi-Gasic

FI Comer

G Majumdar

GW Hart

J Ferlay

L Lupini

LE Raez

M Stein

N Hay

Q Chen

R Lozano

R Shafi

RZ Shang

S Buren

S Corre

S Olivier-Van Stichelen

X Yang

Y Dynkevich

Y Onodera

Oncogenesis

AbstractThe 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, in 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.</jats:p

F Pepe

S Pagotto

S Soliman

C Rossi

P Lanuti

C Braconi

R Mariani-Costantini

R Visone

Crossref

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

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

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