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：
8997477
负责人：
Kathryn Elaine Wellen
金额：
$ 33.2万
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8997477
关键词：
ATP Citrate (pro-S)-Lyase Acetyl Coenzyme A Acetylation Candidate Disease Gene Cell Proliferation Regulation Cells ChIP-seq Chromatin Structure Citrates Data Enzymes Epigenetic Process Event Gene Expression Genes Genome Glioblastoma Glioma Glucose Glycolysis Goals Growth Health Histone Acetylation Histone Deacetylase Inhibitor Human In Vitro Link Location Malignant Neoplasms Mediating Metabolic Metabolism Nuclear Nutrient Oncogenes Oncogenic Pathway interactions Pattern Phosphatidylinositols Phosphorylation Phosphotransferases Play Predisposition Production Regulation Research Role Testing Therapeutic Work cancer cell chromatin modification epigenetic regulation epigenome genome integrity genome-wide glucose uptake histone acetyltransferase in vivo insight interest neoplastic cell novel nutrient metabolism response transcription factor tumor tumor growth tumor metabolism tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Cancer cells are characterized by reprogramming of nutrient metabolism to support growth and proliferation and by epigenetic alterations that impact gene expression and genomic integrity. An emerging paradigm for epigenetic regulation of the genome is that chromatin modifications can be regulated by cellular metabolism. For example, glucose availability and production of acetyl-CoA by the enzyme ATP-citrate lyase (ACL) can modulate global levels of histone acetylation. The effects of oncogene-induced metabolic reprogramming on the cancer cell epigenome are largely unknown, however. The phosphoinositide 3-kinase-Akt pathway is frequently activated in cancer, and is a key regulator of glucose uptake and glycolysis. Akt can also directly activate ACL through phosphorylation, potentially facilitating acetyl-CoA production during nutrient limitation. We hypothesize that Ak-induced metabolic reprogramming influences histone acetylation, thereby impacting gene expression and proliferation in cancer cells. The goals of this proposal are to define the mechanisms linking nutrient availability to histone acetylation and to elucidate the impact of Akt activation on acetyl-CoA production, genome-wide histone acetylation, and gene expression in glioblastoma cells. Three specific aims are proposed: 1) determine the mechanisms underlying ACL-dependent regulation of histone acetylation in cancer cells~ 2) investigate the role of Akt-induced metabolic reprogramming in modulating acetyl-CoA production and utilization in cancer cells~ 3) examine the effects of Akt activation and glucose availability on gene expression and the epigenome.

描述（由申请人提供）：癌细胞的特征是营养代谢重新编程以支持生长和增殖，以及影响基因表达和基因组完整性的表观遗传改变。基因组表观遗传调控的一个新兴范例是染色质修饰可以通过细胞代谢来调节。例如，葡萄糖的利用率和 ATP-柠檬酸裂解酶 (ACL) 产生的乙酰辅酶 A 可以调节组蛋白乙酰化的整体水平。然而，癌基因诱导的代谢重编程对癌细胞表观基因组的影响在很大程度上尚不清楚。磷酸肌醇 3-激酶-Akt 通路在癌症中经常被激活，并且是葡萄糖摄取和糖酵解的关键调节因子。 Akt 还可以通过磷酸化直接激活 ACL，从而可能在营养限制期间促进乙酰辅酶 A 的产生。我们假设 Ak 诱导的代谢重编程影响组蛋白乙酰化，从而影响癌细胞的基因表达和增殖。该提案的目标是定义营养可用性与组蛋白乙酰化之间的联系机制，并阐明 Akt 激活对乙酰辅酶 A 产生、全基因组组蛋白乙酰化和胶质母细胞瘤细胞中基因表达的影响。提出了三个具体目标：1) 确定癌细胞中 ACL 依赖性调节组蛋白乙酰化的机制 ~ 2) 研究 Akt 诱导的代谢重编程在调节癌细胞中乙酰辅酶 A 产生和利用中的作用 ~ 3) 检查Akt 激活和葡萄糖可用性对基因表达和表观基因组的影响。