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

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Abstract

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.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

ChREBP:

Carbohydrate Responsive Element Binding Protein

Co-IP:

Co-immunoprecipitation

DMEM:

Dulbecco’s Modified Eagle’s Medium

DMSO:

Dimethyl sulfoxide

Elovl:

Elongation of very long chain fatty acids proteins

FASN:

Fatty acid synthase

FCS:

Fetal calf serum

GEPIA:

Gene Expression Profiling Interactive Analysis

GFAT-1:

Glutamine:fructose–6–phosphate amidotransferase–1

GPCR:

G protein coupled-receptors

HBP:

Hexosamine biosynthetic pathway

HRP:

Horseradish peroxidase

IHH:

Immortalized human hepatocytes

LPA:

Lysophosphatidic acid

MEF:

Mouse embryonic fibroblasts

MEM:

Minimal Essential Medium

mTOR:

Mechanistic target of rapamycin

NaDOC:

Sodium deoxycholate

OD:

Optical density

OGA:

O-GlcNAcase

OGT:

O-GlcNAc transferase

p70S6K:

p70 Ribosomal protein S6 Kinase

PAF:

Paraformaldehyde

PBS:

Phosphate-Buffered Saline

PIP3:

Phosphatidylinositol–3,4,5–triphosphate

PLA:

Proximity ligation assay

PRAS40:

Proline-rich AKT substrate of 40 kDa

PTEN:

Phosphatase and tensin homolog

PTM:

Post-translational modification

rpS6:

Ribosomal protein S6

RT:

Room temperature

RT-qPCR:

Reverse transcription-quantitative polymerase chain reaction

SDS:

Sodium dodecyl sulfate

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

siRNA:

Small interfering RNA

SREBP:

Sterol Responsive Element Binding Protein

TBS:

Tris-buffered saline

VLDL:

Very low density lipoproteins

WB:

Western blot

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Acknowledgements

We are grateful to Dr. Julien Thévenet (INSERM, CHU Lille, UMR1190 Translational Research for Diabetes, European Genomic Institute for Diabetes, Lille, France) for helping in harvesting livers form C57Bl6 and ob/ob mice. We also thank Pr. David Vocadlo and Dr. Matthew Alteen from the Simon Fraser University for providing Ac5SGlcNAc and the SFR-Necker small animal histology and morphology platform for histological slide preparation.

Funding

This research was supported by the University of Lille, the “Centre National de la Recherche Scientifique (CNRS)” and from the “Agence Nationale de la Recherche” (ANR-JCJC-NUTRISENSPIK-16-CE14-0029) to G.P. SR is a recipient of a fellow from the “Ministère de l’Enseignement Supérieur et de la Recherche” and from the “Région Hauts-de-France”.

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Authors and Affiliations

  1. Université de Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59000, Lille, France

    Sadia Raab, Ninon Very, Steffi Baldini, Céline Schulz, Marlène Mortuaire, Quentin Lemaire, Stéphan Hardivillé, Ikram El Yazidi-Belkoura, Anne-Sophie Vercoutter-Edouart & Tony Lefebvre

  2. Institut Necker-Enfants Malades (INEM), INSERM U1151/CNRS UMR 8253, Université de Paris , 75014, Paris, France

    Alexis Gadault & Ganna Panasyuk

  3. Université de Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, 59000, Lille, France

    Amélie Decourcelle & Vanessa Dehennaut

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  1. Sadia Raab
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Correspondence to Tony Lefebvre.

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The authors declare neither conflict of interest nor competing interests.

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All procedures were carried out according to the French guidelines for the care of experimental animals. Experimental procedure was approved by the Animal Care Committee of the French Research Ministry (Autor. APAFiS #1879-2018121918307521 and A75-14-08).

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Raab, S., Gadault, A., Very, N. et al. Dual regulation of fatty acid synthase (FASN) expression by O-GlcNAc transferase (OGT) and mTOR pathway in proliferating liver cancer cells. Cell. Mol. Life Sci. 78, 5397–5413 (2021). https://doi.org/10.1007/s00018-021-03857-z

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  • DOI: https://doi.org/10.1007/s00018-021-03857-z

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