# Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer

> **NIH NIH R03** · UNIVERSITY OF KENTUCKY · 2022 · $76,500

## Abstract

PROJECT SUMMARY
Altered metabolism is rapidly emerging as a target for therapeutic intervention in cancer. An increased rate of
lipid synthesis in cancer has been recognized as an important aspect of rewired metabolism in transformed
cells. Fatty acid synthase (FASN), a key enzyme of lipid synthesis, is actively investigated in pre-clinical
studies and clinical trials as a therapeutic target for cancer. Altered glycosylation, also a universal feature of
cancer, is associated with cancer progression, reduced immune response, and resistance to drug treatments.
The hexosamine biosynthesis pathway (HBP) generates a nucleotide sugar, uridine diphosphate N-
acetylglucosamine (UDP-GlcNAc), a key substrate for protein glycosylation. However, the mechanisms of how
upregulation of de novo lipid synthesis can contribute to synthesis of UDP-GlcNAc and the effect of FASN-
targeted therapy on hexasomine biosynthesis are not yet understood. We developed colorectal cancer (CRC)
mouse models with heterozygous and homozygous deletion of FASN in intestine and colon and found that
deletion of FASN is associated with a significant decrease in tumor number and an increase in mouse survival.
The RNA-seq data and metabolic analysis of tumors show that FASN selectively regulates the levels of
enzymes and metabolites within the HBP. Consistantly, we found that expression of FASN alters synthesis of
UDP-GlcNAc in human CRC cells and correlates with UDP-GlcNAc level in human CRC tissues. Furthermore,
we show that FASN alters O-linked and N-linked protein glycosylation. Therefore, we hypothesize that
upregulation of FASN during tumorigenesis enhances synthesis of UDP-GlcNAc via rewiring the metabolic
network in CRC cells. In Aim 1, using stable isotope labeling and ultrahigh-resolution mass-spectrometry and
nuclear magnetic resonance, we will delineate FASN-mediated metabolic changes in polar metabolites of
multiple pathways that supply metabolic subunits to UDP-GlcNAc in vivo. In Aim 2, we will determine the effect
of pharmacological inhibition of FASN on synthesis of UDP-GlcNA in human CRC organoids and established
the link between expression of FASN and enzymes within the HBP in human CRC tissues. Knowledge of how
FASN regulates UDP-GlcNAc synthesis will have a significant translational impact by contributing to better
understanding of the mechanisms of metabolic adoptations in cancer cells and identifying new targetable
liabilities that would lead to development of more effective therapeutic strategies for CRC. Completion of these
studies will also help us advance our ongoing research to better understand how lipid synthesis regulates the
landscape of glycosylation in CRC and contribution of these metabolic pathways to CRC progression and
metastasis.

## Key facts

- **NIH application ID:** 10437880
- **Project number:** 5R03CA262720-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** YEKATERINA ZAYTSEVA
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $76,500
- **Award type:** 5
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10437880

## Citation

> US National Institutes of Health, RePORTER application 10437880, Fatty acid synthase in regulation of UDP-GlcNAc synthesis in colorectal cancer (5R03CA262720-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10437880. Licensed CC0.

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