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

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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.