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

描述（由申请人提供）：癌细胞的特征是通过营养代谢的重编程来支持生长和增殖，以及通过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式是染色质修饰可以通过细胞代谢调节。例如，葡萄糖的可用性和柠檬酸atp裂解酶（ACL）乙酰辅酶a的产生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是未知的。磷酸肌肽3-激酶- akt通路在癌症中经常被激活，是葡萄糖摄取和糖酵解的关键调节因子。Akt也可以通过磷酸化直接激活ACL，可能促进营养限制时乙酰辅酶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，从而影响癌细胞中的基因表达和增殖。本研究的目标是确定营养素可用性与组蛋白乙酰化之间的联系机制，并阐明Akt激活对胶质母细胞瘤细胞中乙酰辅酶a产生、全基因组组蛋白乙酰化和基因表达的影响。本文提出了三个具体目标：1)确定癌细胞中依赖于acl的组蛋白乙酰化调控的机制；2)研究Akt诱导的代谢重编程在调节癌细胞中乙酰辅酶a的产生和利用中的作用；3)研究Akt激活和葡萄糖可用性对基因表达和表观基因组的影响。

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.