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

脂肪酸合酶在结直肠癌中调节 UDP-GlcNAc 合成

• 批准号: 10437880
• 负责人: YEKATERINA ZAYTSEVA
• 金额: $ 7.65万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437880
• 关键词: Acetyl Coenzyme A; Acyl Coenzyme A; Adopted; Amino Sugars; Anabolism; Biochemical Pathway; Cancer Etiology; Cell Proliferation; Cessation of life; Characteristics; Clinical Trials; Colon; Colorectal Cancer; Data; Development; Disease; Disease-Free Survival; Drug resistance; Enzymes; Fatty Acids; Fatty-acid synthase; Funding; Gene Expression; Genes; Genetic; Glucose; Glutamine; Glycolysis; Growth; Hexosamines; Human; Immune response; Intestines; Knowledge; Lead; Link; Lipids; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Metabolic; Metabolic Pathway; Metabolism; Mus; Neoplasm Metastasis; Nitrogen; Nuclear Magnetic Resonance; Organoids; Pathway interactions; Pharmacology; Pharmacotherapy; Phase II Clinical Trials; Post-Translational Protein Processing; Process; Production; Prognosis; Protein Glycosylation; Regulation; Research; Resolution; Role; Signal Transduction; Solid; Stable Isotope Labeling; Testing; Therapeutic; Therapeutic Intervention; Tissues; United States; Up-Regulation; Uridine Diphosphate N-Acetylglucosamine; Woman; anti-cancer; cancer cell; cell transformation; colorectal cancer progression; glycosylation; improved; in vivo; inhibitor; link protein; lipid biosynthesis; long chain fatty acid; men; mouse model; neoplastic cell; novel; novel therapeutic intervention; overexpression; oxidation; preclinical study; sugar nucleotide; targeted treatment; therapeutic target; therapeutically effective; transcriptome sequencing; translational impact; tumor; tumor progression; tumorigenesis; uptake

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.

项目总结 新陈代谢改变正在迅速成为癌症治疗干预的目标。增加的比率 癌症中的脂质合成已被认为是转化中重新连接代谢的一个重要方面 细胞。脂肪酸合酶(FASN)是脂质合成的关键酶，临床前研究十分活跃。 作为癌症治疗靶点的研究和临床试验。改变的糖基化，也是一个普遍的特征 癌症，与癌症进展、免疫反应降低和药物治疗耐药有关。 己糖胺的生物合成途径(HBP)产生一种核苷酸糖，尿苷二磷酸-N- 乙酰氨基葡萄糖(UDP-GlcNAc)，蛋白质糖基化的关键底物。然而，其机制是如何 上调从头合成脂质可促进UDP-GlcNAc的合成及FASN-1的作用 针对己糖胺生物合成的靶向治疗尚不清楚。我们患上了结直肠癌(CRC) 肠道和结肠FASN杂合性和纯合性缺失的小鼠模型发现 FASN的缺失与肿瘤数量的显著减少和小鼠存活率的增加有关。 Rna-seq数据和肿瘤代谢分析表明，FASN选择性地调节 HBP内的酶和代谢物。一致地，我们发现FASN的表达改变了 UDP-GlcNAc在人结直肠癌细胞中的表达，并与人结直肠癌组织中UDP-GlcNAc水平相关。此外， 我们发现FASN改变了O-连接和N-连接的蛋白质的糖基化。因此，我们假设 FASN在肿瘤发生过程中的上调通过重新连接代谢促进UDP-GlcNAc的合成 CRC小区中的网络。在目标1中，使用稳定同位素标记和超高分辨率质谱学和 核磁共振，我们将描绘FASN介导的极性代谢物的代谢变化 体内向UDP-GlcNAc提供代谢亚单位的多种途径。在目标2中，我们将确定 FASN对人结直肠癌有机体合成UDP-GlcNA的药理抑制作用 人类结直肠癌组织中FASN的表达与HBP中的酶之间的联系。了解如何 FASN调节UDP-GlcNAc合成将通过有助于更好地 肿瘤细胞代谢采纳机制的认识及新靶点的确定 将导致为结直肠癌制定更有效的治疗策略的责任。完成这些工作 研究还将帮助我们推进正在进行的研究，以更好地了解脂质合成如何调节 糖基化在结直肠癌中的地位以及这些代谢途径对结直肠癌进展和 转移。