O-GlcNAcylation of Fatty Acid Synthase is required for its proper subcellular localization, expression level and activity

Journal home page for Journal of Biological ChemistryAuthor links open overlay panel, , , , , , , , , , , Abstract

Fatty Acid Synthase (FASN) is involved in various fundamental cellular processes through its pivotal role in producing fatty acids through the de novo lipogenesis pathway. FASN is frequently overexpressed in tumors and participates in cancer cell proliferation. Little has been documented regarding post-translational modifications of FASN. We previously demonstrated that O-GlcNAcylation regulates FASN in mice livers and in the HepG2 hepatic cancer cell line. In the present study, we show that modulation of global O-GlcNAcylation levels impacts fatty acids production in HepG2 cells. We identified serine 595 and threonine 980 as major O-GlcNAcylation sites. While mutation of S595 moderately affects FASN behavior, T980 is crucial for FASN expression, membrane localization, homodimerization, stability and activity in Hep3B cells. This residue is necessary for FASN properties, promoting cell survival, cell proliferation and cell cycle progression. Our results suggest that targeting FASN at T980, may open an interesting path for controlling its catalytic activity.

Key-words

Fatty acid synthase

fatty acids

O-GlcNAcylation

O-GlcNAc transferase

liver cancer cells

® 2025 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology.

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