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

• 批准号: 10377406
• 负责人: Kathryn Elaine Wellen
• 金额: $ 37.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10377406
• 关键词: AKT inhibition; ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetyl Coenzyme A; Acetylation; Anabolism; Automobile Driving; Blood Circulation; Cell Proliferation; Cell Survival; Cells; Chemoresistance; 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; Prognosis; 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; disease prognosis; epigenome; flexibility; high risk; improved; in vivo; insulin mediators; insulin signaling; metabolome; mevalonate; mouse model; mutant; new therapeutic target; nutrition; pancreatic ductal adenocarcinoma cell; pancreatic tumorigenesis; prevent; response; treatment response; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; tumorigenesis

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.

项目总结 胰腺导管腺癌(PDA)预后很差，这主要是由于它 转移较早，通常发现较晚，此时肿瘤不能再切除。肥胖症增加 个体发生动脉导管未闭的风险，尽管驱动这种联系的机制还知之甚少。这 Proposal研究了PDA细胞中的胰岛素信号促进代谢改变和 促进肿瘤发展和进展的基因表达变化，可能指向 在高危人群中预防PDA或改善PDA治疗结果的新战略。 组蛋白乙酰化对乙酰基供体乙酰辅酶A的可用性和我们以前的工作高度敏感 已经明确了代谢酶三磷酸腺苷-柠檬酸裂解酶(ACLY)在组蛋白乙酰化调节中的作用 在不同的哺乳动物细胞类型中的水平。组蛋白乙酰化在PDA肿瘤发生中起关键作用，尽管 驱动改变的组蛋白乙酰化的机制还不是很清楚。在初步研究中，我们有 发现胰岛素和胰岛素样生长因子(IGF)刺激PDA细胞可导致ACLY Ser455 磷酸化，增加其活性，以及全球组蛋白乙酰化水平的提高。ACLY是 AKT下游被磷酸化，AKT抑制在全球范围内抑制组蛋白乙酰化，并在癌症- 相关的轨迹。我们假设升高的胰岛素/胰岛素样生长因子水平促进代谢和转录 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/胰岛素样生长因子的作用 在KRAS突变的PDA细胞中代谢和表观遗传重塑中的信号传递 假设驱动和不偏不倚的方法。最后，我们将测试ACLY在调节肥胖相关因素中的作用 胰腺肿瘤的发生以及靶向乙酰辅酶A依赖过程抑制肿瘤的可能性 生长和改善治疗反应。本研究将阐明新的机制，通过 代谢影响细胞代谢和肿瘤表观基因组。这项研究的发现具有潜在的潜力 为PDA患者的营养建议提供机械原理和/或确定新的 预防手术切除后肿瘤复发的治疗靶点或联合应用 化疗以提高其疗效。