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

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 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.