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.
Document Type
Article
Publication Date
4-30-2024
Digital Object Identifier (DOI)
https://doi.org/10.3390/ijms25094883
Funding Information
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.).
Repository Citation
Drury, James; Geisen, Mariah E.; Tessmann, Josiane Weber; Rychahou, Piotr G.; and Kelson, Courtney O., "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" (2024). Markey Cancer Center Faculty Publications. 186.
https://uknowledge.uky.edu/markey_facpub/186
Notes/Citation Information
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).