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 language | English |
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Article number | 4883 |
Journal | International Journal of Molecular Sciences |
Volume | 25 |
Issue number | 9 |
DOIs | |
State | Published - 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.).
Funders | Funder number |
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University of Kentucky Markey Cancer Center | |
University of Kentucky (UK) Superfund Research Center | |
National Childhood Cancer Registry – National Cancer Institute | P30 CA177558, T32 CA165990, R01 CA249734 |
National Childhood Cancer Registry – National Cancer Institute | |
National Institutes of Health/National Institute of Environmental Health Sciences | P42 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