Overexpression of Fatty Acid Synthase Upregulates Glutamine–Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth

James Drury, Mariah E. Geisen, Josiane Weber Tessmann, Piotr G. Rychahou, Courtney O. Kelson, Daheng He, Chi Wang, B. Mark Evers, Yekaterina Y. Zaytseva

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1 Scopus citations

Abstract

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood. Here, for the first time, we show that overexpression of FASN increases the expression of glutamine–fructose-6-phosphate transaminase 1 (GFPT1) and O-linked N-acetylglucosamine transferase (OGT), enzymes involved in hexosamine metabolism, and the level of O-GlcNAcylation in vitro and in vivo. Consistently, expression of FASN significantly correlates with expression of GFPT1 and OGT in human CRC tissues. shRNA-mediated downregulation of GFPT1 and OGT inhibits cellular proliferation and the level of protein O-GlcNAcylation in vitro, and knockdown of GFPT1 leads to a significant decrease in tumor growth and metastasis in vivo. Pharmacological inhibition of GFPT1 and OGT leads to significant inhibition of cellular proliferation and colony formation in CRC cells. In summary, our results show that overexpression of FASN increases the expression of GFPT1 and OGT as well as the level of protein O-GlcNAcylation to promote progression of CRC; targeting the hexosamine biosynthesis pathway could be a therapeutic approach for this disease.

Original languageEnglish
Article number4883
JournalInternational Journal of Molecular Sciences
Volume25
Issue number9
DOIs
StatePublished - May 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.

Funding

University of Kentucky Markey Cancer Center\u2019s Biostatistics and Bioinformatics Shared Resource Facility provided statistical analysis of human data (supported by National Cancer Institute grant P30 CA177558). The Markey Cancer Center\u2019s Research Communications Office provided assistance with manuscript preparation. This research was funded by NCI R01 CA249734 (Y.Z.), NCI training grant T32 CA165990 (C.K.) and NIEHS P42 ES007380 (University of Kentucky Superfund Research Center, Project 1-Y.Z.).

FundersFunder number
University of Kentucky Markey Cancer Center
University of Kentucky (UK) Superfund Research Center
National Childhood Cancer Registry – National Cancer InstituteP30 CA177558, T32 CA165990, R01 CA249734
National Childhood Cancer Registry – National Cancer Institute
National Institutes of Health/National Institute of Environmental Health SciencesP42 ES007380
National Institutes of Health/National Institute of Environmental Health Sciences

    Keywords

    • O-GlcNAcylation
    • colorectal cancer
    • fatty acid synthase
    • hexosamine biosynthesis

    ASJC Scopus subject areas

    • Catalysis
    • Molecular Biology
    • Spectroscopy
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Inorganic Chemistry

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