Role of Akt-regulated acetyl-CoA metabolism in altering the cancer cell epigenome

Akt 调节的乙酰辅酶 A 代谢在改变癌细胞表观基因组中的作用

• 批准号: 8908400
• 负责人: Joyce Vivian Lee
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908400
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acetylation; Acute; Binding; Cancer Cell Growth; Cell Line; Cell Proliferation; Cell Survival; Cells; Chromatin; Citrates; Data; Development; Fatty Acids; Gene Expression; Generations; Genes; Genome; Glioblastoma; Glucose; Goals; Growth; Growth Factor; Histone Acetylation; Human; In Vitro; Lesion; Light; Lipids; Malignant Neoplasms; Mammary gland; Metabolic; Metabolism; Mitochondria; Nutrient; Oncogene Activation; Oncogenes; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphotransferases; Process; Production; Protein Acetylation; Proteus; Proto-Oncogene Proteins c-akt; RNA Sequences; Recurrence; Regulation; Regulator Genes; Reporting; Risk; Role; Serine; Signal Transduction; Stress; Supplementation; Survival Rate; Testing; Tissues; Work; Yeast Model System; Yeasts; beta catenin; cancer cell; cancer type; cell growth; cell type; epigenome; extracellular; glucose uptake; histone acetyltransferase; in vivo; in vivo Model; malignant breast neoplasm; neoplastic cell; novel therapeutics; outcome forecast; programs; promoter; public health relevance; research study; signal processing; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment; tumor progression; vector control

 DESCRIPTION (provided by applicant): Altered histone acetylation is evident in many human malignancies. In glioblastoma and other cancers, increased histone acetylation is reported to correlate with poorer patient prognosis. Generally, tumor cell histone acetylation is regulated in a glucose-dependent manner, through ATP-citrate-lyase (ACLY)-dependent conversion of glucose-derived citrate into acetyl-CoA, the acetyl-donor for protein acetylation. In low glucose conditions, acetyl-CoA levels decrease and become limiting for histone acetylation. Concomitant decreases in expression of pro-growth genes mirror the reduction in global and promoter-specific histone acetylation. Importantly, supplementation of acetate can rescue intracellular pools of acetyl-CoA, histone acetylation, and restore growth promoting gene expression. These findings suggest that acetyl-CoA functions as a direct regulator of gene expression in tumors. However, the precise mechanisms for this regulation are not clear. Protein kinase B (Akt/PKB) is commonly activated in cancer cells, promoting higher glucose uptake and acetyl-CoA production by increasing ACLY enzymatic activity through phosphorylation (S455). Indeed, Akt activation leads to increased histone acetylation and phosphorylation of ACLY in vitro and in vivo. Notably, Akt activation leads to sustained histone acetylation in several cancer types, regardless of extracellular glucose concentrations. Our findings suggest that tumor metabolic reprogramming via Akt activation alters cellular phenotypes via modulation of acetyl-CoA concentrations. Broadly speaking, oncogene-induced alterations in acetyl-CoA-dependent histone acetylation could potentially impact several chromatin-dependent processes, such as gene expression, and influence cancer cell growth and survival in fluctuating microenvironments. The goals of this project are to examine the role of acetyl-CoA in cancer cells with Akt activation. Extra-mitochondrial acetyl-CoA is utilized in lipid synthesis and protei acetylation. It is unclear whether partitioning of acetyl-CoA between lipid synthesis and histone acetylation in the setting of fluctuating nutrient conditions impacts cell growth or survival. Experiments in aim 1 will determine whether acetyl-CoA utilization for histone acetylation or lipid synthesis is a contributor to Akt's survival program. Experiments in aim 2 will investigate the mechanisms by which acetyl-CoA concentrations modulate gene expression. From a list of top acetyl-CoA regulated genes identified by RNA-sequencing, I will determine whether the expression of these genes are regulated by acetyl-CoA, through acetylation at gene promoters and/or via acetylation-dependent regulation of transcription factor recruitment to chromatin. It i becoming increasingly apparent that acetyl-CoA sits at the hub of both metabolic and signaling processes within the cell, as its concentrations are modulated by both extracellular nutrient availability and growth factor signaling. The aims outlined in this project will shed light on the contribution of these processes to tumor growth and survival.