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: 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
• 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

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.

项目摘要 胰腺导管腺癌（PDA）的预后很差，这主要是因为它 早期转移，并且通常在肿瘤不能再被切除时被检测到。肥胖会增加 个人发展PDA的风险，虽然驱动这种联系的机制知之甚少。这 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， 基因表达的变化，促进肿瘤的发展和进展，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供体乙酰辅酶A的可用性高度敏感，我们以前的工作 已经确定了代谢酶ATP-柠檬酸裂解酶（ACLY）在组蛋白乙酰化调节中的作用 在不同的哺乳动物细胞类型的水平。组蛋白乙酰化在PDA肿瘤发生中起关键作用， 驱动改变的组蛋白乙酰化的机制还没有被很好地理解。在初步研究中， 发现胰岛素和胰岛素样生长因子（IGF）刺激PDA细胞导致ACLY Ser 455 磷酸化，增加其活性，以及整体组蛋白乙酰化水平升高。ACLY是 在AKT的下游磷酸化，并且AKT抑制抑制组蛋白乙酰化在整体上和在癌症- 相关位点。我们假设升高的胰岛素/IGF水平促进代谢和转录， 在PDA细胞中重塑，促进肿瘤进展。为了验证这一点，我们将定义胰岛素/IGF的作用， 使用以下组合在KRAS突变PDA细胞中进行代谢和表观遗传重塑的信号传导 假设驱动和无偏见的方法。最后，我们将测试ACLY在介导肥胖相关的 胰腺肿瘤发生，以及靶向乙酰辅酶A依赖性过程抑制肿瘤的潜力 生长并改善治疗反应。这项研究将阐明新的机制，通过系统 代谢影响细胞代谢和肿瘤表观基因组。这项研究的结果有可能 为PDA患者的营养建议提供机械原理和/或识别新的 预防手术切除后肿瘤复发的治疗靶点或与 化疗，以提高其疗效。