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

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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.