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

描述(申请人提供)：癌细胞的特征是营养代谢的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变化。基因组表观遗传调控的一个新范式是染色质修饰可以由细胞新陈代谢来调节。例如，葡萄糖的可获得性和三磷酸腺苷-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是未知的。肌醇磷脂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还可以通过磷酸化直接激活ACL，在营养限制期间潜在地促进乙酰辅酶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。这项建议的目的是明确营养供应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基因表达的影响。我们提出了三个具体的目标：1)确定癌细胞中组蛋白乙酰化的依赖于acl的调控机制；2)研究Akt诱导的代谢重编程在调节癌细胞乙酰辅酶A生产和利用中的作用；3)检测Akt激活和葡萄糖供应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.