Role of acetyl-CoA in linking cancer cell metabolism and epigenetics

乙酰辅酶A在连接癌细胞代谢和表观遗传学中的作用

基本信息

批准号：
9973530
负责人：
Kathryn Elaine Wellen
金额：
$ 39.76万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9973530
关键词：
AKT inhibition ATP Citrate (pro-S)-Lyase Acetate-CoA Ligase Acetyl Coenzyme A Acetylation Adenocarcinoma Cell Anabolism Automobile Driving Blood Circulation Cell Proliferation Cell Survival Cells Data Development Diagnosis Disease Enzymes Epigenetic Process Excision Exposure to Gene Expression Gene Expression Regulation Genetic Genetic Models Genetic Transcription Health Benefit Histone Acetylation Human Hyperinsulinism Impairment Incidence Individual Insulin KRAS2 gene Link Lysine Malignant Neoplasms Malignant neoplasm of pancreas Mammalian Cell Mediating Metabolic Metabolism Modeling Mus Neoplasm Metastasis Nutritional Obesity Operative Surgical Procedures Pancreas Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Pharmacology Phosphorylation Play Populations at Risk Prevention strategy Primary Neoplasm Process Production Proto-Oncogene Proteins c-akt Public Health Reading Recommendation Recurrence Regulation Resected Resistance Risk Role Signal Transduction Somatomedins Supporting Cell Testing Therapeutic Therapeutic Intervention Transcription Alteration Treatment Efficacy Treatment outcome Unresectable Work advanced disease barrier to care cancer cell cell type chemotherapy epigenome flexibility high risk improved in vivo insulin mediators insulin signaling metabolome mevalonate mouse model mutant new therapeutic target nutrition outcome forecast pancreatic tumorigenesis prevent response treatment response tumor tumor growth tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, due largely to the fact that it metastasizes early and is typically detected late, when tumors can no longer be resected. Obesity increases an individual’s risk of developing PDA, although the mechanisms driving this link are poorly understood. This proposal investigates the hypothesis that insulin signaling in PDA cells promotes metabolic alterations and changes in gene expression that facilitate tumor development and progression, potentially pointing towards new strategies to prevent PDA in at-risk populations or to improve PDA treatment outcomes. Histone acetylation is highly sensitive to the availability of the acetyl donor acetyl-CoA, and our previous work has defined a role for the metabolic enzyme ATP-citrate lyase (ACLY) in the regulation of histone acetylation levels in diverse mammalian cell types. Histone acetylation plays key roles in PDA tumorigenesis, although the mechanisms that drive altered histone acetylation are not well understood. In preliminary studies, we have found that insulin and insulin-like growth factor (IGF) stimulation of PDA cells results in ACLY Ser455 phosphorylation, increasing its activity, as well as elevated levels of global histone acetylation. ACLY is phosphorylated downstream of AKT, and AKT inhibition suppresses histone acetylation globally and at cancer- relevant loci. We hypothesize that elevated insulin/IGF levels promote metabolic and transcriptional remodeling in PDA cells, promoting tumor progression. To test this, we will define the role of insulin/IGF signaling in metabolic and epigenetic remodeling in KRAS mutant PDA cells, using a combination of hypothesis-driven and unbiased approaches. Finally, we will test the role of ACLY in mediating obesity-linked pancreatic tumorigenesis, as well as the potential to target acetyl-CoA-dependent processes to suppress tumor growth and improve therapeutic responses. This study will elucidate new mechanisms through which systemic metabolism influences cellular metabolism and the tumor epigenome. Findings from this study have potential to provide a mechanistic rationale for nutritional recommendations for PDA patients and/or to identify new therapeutic targets to prevent tumor recurrence after surgical resection or to use in conjunction with chemotherapy to improve its efficacy.

项目概要胰腺导管腺癌 (PDA) 的预后很差，这主要是因为它转移较早，通常在肿瘤无法再切除时才被发现。肥胖增加。个人患上 PDA 的风险，尽管人们对这种联系的机制知之甚少。该提案调查了 PDA 细胞中胰岛素信号传导促进代谢改变的假设促进肿瘤发展和进展的基因表达变化，可能指向预防高危人群 PDA 或改善 PDA 治疗结果的新策略。组蛋白乙酰化对乙酰基供体乙酰辅酶 A 的可用性高度敏感，我们之前的工作确定了代谢酶 ATP-柠檬酸裂解酶 (ACLY) 在组蛋白乙酰化调节中的作用然而，组蛋白乙酰化在不同哺乳动物细胞类型中的水平在 PDA 肿瘤发生中发挥着关键作用。在初步研究中，我们还不清楚驱动组蛋白乙酰化改变的机制。发现胰岛素和胰岛素样生长因子 (IGF) 刺激 PDA 细胞会导致 ACLY Ser455 磷酸化，增加其活性，以及整体组蛋白乙酰化水平升高。 AKT 下游磷酸化，抑制 AKT 可抑制全局和癌症中的组蛋白乙酰化我们追求胰岛素/IGF水平升高促进代谢和转录。 PDA 细胞重塑，促进肿瘤进展为了测试这一点，我们将定义胰岛素/IGF 的作用。 KRAS 突变 PDA 细胞代谢和表观遗传重塑中的信号传导，使用以下组合最后，我们将测试 ACLY 在调节肥胖相关方面的作用。胰腺肿瘤的发生，以及靶向乙酰辅酶A依赖性过程来抑制肿瘤的潜力这项研究将阐明系统性的新机制。代谢影响细胞代谢和肿瘤表观基因组。这项研究的结果具有潜力。为 PDA 患者的营养建议提供机械原理和/或确定新的目标是防止手术切除后肿瘤复发或与化疗以提高其疗效。