Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells

Autor: Alexis Gadault, Anne-Sophie Vercoutter-Edouart, Ninon Very, Amélie Decourcelle, Tony Lefebvre, Ganna Panasyuk, Ikram El Yazidi-Belkoura, Stéphan Hardivillé, Céline Schulz, Marlène Mortuaire, Quentin Lemaire, Sadia Raab, Steffi Baldini, Vanessa Dehennaut
Přispěvatelé: Université de Lille, CNRS, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 [UGSF], Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)], Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 [UGSF], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER], Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE14-0029,NUTRISENSPIK,Déterminants moléculaires de l'homéostasie hépatique nutritive(2016), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Rok vydání: 2021
Předmět:
Male
Carcinoma
Hepatocellular
[SDV]Life Sciences [q-bio]
Cell
Mice
Obese
Apoptosis
N-Acetylglucosaminyltransferases
Cell proliferation
Protein interactions
Proximity ligation assay
siRNA
Ob/ob mice
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
Biomarkers
Tumor
Tumor Cells
Cultured
medicine
Animals
Humans
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Pharmacology
0303 health sciences
biology
Cell growth
Chemistry
TOR Serine-Threonine Kinases
Liver Neoplasms
030302 biochemistry & molecular biology
Cell Biology
Cell cycle
Xenograft Model Antitumor Assays
3. Good health
Cell biology
Fatty Acid Synthase
Type I
Gene Expression Regulation
Neoplastic
Mice
Inbred C57BL
[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry
Fatty acid synthase
medicine.anatomical_structure
Cancer cell
biology.protein
Molecular Medicine
Signal transduction
Zdroj: Cellular and Molecular Life Sciences
Cellular and Molecular Life Sciences, Springer Verlag, 2021, Cellular and Molecular Life Sciences, 78 (10), ⟨10.1007/s00018-021-03857-z⟩
Cellular and Molecular Life Sciences, 2021, Cellular and Molecular Life Sciences, 78 (10), ⟨10.1007/s00018-021-03857-z⟩
ISSN: 1420-9071
1420-682X
DOI: 10.1007/s00018-021-03857-z
Popis: International audience; Fatty acid synthase (FASN) participates in many fundamental biological processes, including energy storage and signal transduction, and is overexpressed in many cancer cells. We previously showed in a context of lipogenesis that FASN is protected from degradation by its interaction with O-GlcNAc transferase (OGT) in a nutrient-dependent manner. We and others also reported that OGT and O-GlcNAcylation up-regulate the PI3K/AKT/mTOR pathway that senses mitogenic signals and nutrient availability to drive cell cycle. Using biochemical and microscopy approaches, we show here that FASN co-localizes with OGT in the cytoplasm and, to a lesser extent, in the membrane fraction. This interaction occurs in a cell cycle-dependent manner, following the pattern of FASN expression. Moreover, we show that FASN expression depends on OGT upon serum stimulation. The level of FASN also correlates with the activation of the PI3K/AKT/mTOR pathway in hepatic cell lines, and in livers of obese mice and in a chronically activated insulin and mTOR signaling mouse model (PTEN-null mice). These results indicate that FASN is under a dual control of O-GlcNAcylation and mTOR pathways. In turn, blocking FASN with the small-molecule inhibitor C75 reduces both OGT and O-GlcNAcylation levels, and mTOR activation, highlighting a novel reciprocal regulation between these actors. In addition to the role of O-GlcNAcylation in tumorigenesis, our findings shed new light on how aberrant activity of FASN and mTOR signaling may promote the emergence of hepatic tumors.
Databáze: OpenAIRE
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