Acetyl-CoA metabolism in cancer

Abstract

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

Figure 1.. Compartmentalized acetyl-CoA production pathways.

Mitochondrial acetyl-CoA is generated in many cell types from glucose during anabolic conditions, and from other nutrients, such as long and medium chain fatty acids, acetate, amino acids and beta-hydroxybutyrate, during catabolic conditions, though different cell and tissue types have different nutrient preferences. Pyruvate enters mitochondria through the mitochondrial pyruvate carrier (MPC) and undergoes oxidative decarboxylation by pyruvate dehydrogenase complex (PDC) yielding acetyl-CoA, NADH and CO₂. Fatty acids are transported into mitochondria as acyl-carnitines via the Cpt1/Cpt2 shuttling system, which operates between the mitochondrial outer and inner membranes (not shown). Peroxisomes can also generate short chain fatty acids that are delivered to mitochondria; medium chain fatty acids do not require the acyl-carnitine shuttle. Acetyl group carbons enter the TCA cycle following a condensation reaction with oxaloacetate catalyzed by citrate synthase (CS). TCA cycle flux generates CO₂ and the reducing equivalents that drive the electron transport chain (ETC) and ATP synthesis. Cytosolic acetyl-CoA is used for fatty acid synthesis and in the mevalonate pathway. Cytosolic acetyl-CoA carbons are transferred from mitochondrial citrate via the mitochondrial citrate carrier (Slc25a1). Citrate is cleaved by ATP Citrate Lyase (ACLY) to make cytosolic acetyl-CoA. Citrate may also be generated through reductive carboxylation by the isocitrate dehydrogenases (IDH1/IDH2). Alternatively, cytosolic acetyl-CoA can be derived from acetate via acyl-CoA short-chain synthetase-2 (ACSS2). Acetyl-CoA generated in the cytosol may diffuse into the nucleus for histone acetylation reactions. However, ACLY, ACSS2, and PDC have all been reported in the nucleus where they may generate local acetyl-CoA.

Figure 2.. Regulation of acetyl-CoA metabolic enzymes

(A) Transcriptional and post-translational regulation of acetyl-CoA metabolic enzymes. (B) Impact of oncogenic, microenvironmental and systemic metabolic factors on regulation of acetyl-CoA metabolic enzymes (red, signals associated with oncogenic signaling, high nutrient availability and fatty acid synthesis; green, signals associated with high lipid availability and fatty acid oxidation, and may be linked to obesity-related cancers; blue, signals associated with nutrient stress-inducing adaptation within the tumor microenvironment, which may include fatty acid oxidation or fatty acid synthesis depending on the context). Each of these adaptations may support tumor growth and/or facilitate survival within the tumor microenvironment.

Figure 3.. Acetyl-CoA pathways have roles in ferroptosis protection.

Ferroptosis is a form of regulated cell death driven by iron-dependent phospholipid peroxidation of membrane PUFAs. If these toxic phospholipid peroxides (PLOOH) are not neutralized by ferroptosis defense mechanisms, they can propagate and damage cell membranes, inducing a unique form of cell death. Many cancer cells, due to their unique metabolic properties and propensity for high ROS production, must engage ferroptosis defense mechanisms to survive. Therefore, ferroptosis may be a targetable vulnerability in many tumor types. Several pathways protect against ferroptosis by reducing lipid peroxides. The major defense pathway is the selenoenzyme glutathione peroxidase 4 (GPX4) pathway, which uses glutathione (GSH) to reduced PLOOH. Additional protection is mediated by squalene and ubiquinol (CoQH), both of which are produced from acetyl-CoA via the mevalonate pathway. FSP1 and DHODH have been show to function in this context by reducing ubiquinone (CoQ) to ubiquinol at different locations in the cell. Ferroptosis sensitivity may also be reduced by actively synthesizing and replacing PUFAs with saturated and monounsaturated fatty acids that are resistant to ferroptosis, which is another mechanism linked to acetyl-CoA production. Ferroptosis regulators for which inhibitors are being considered are indicated with a (*). Currently, the most widely studied inhibitors either target solute carrier family 7 member 11 (SLCA11), which controls cystine uptake and glutathione production (e.g. Erastin and its analogs), or GPX4 (e.g. RSL3, ML162, ML210). It will be interesting to see if ACLY or ACSS2 inhibitors synergize with ferroptosis pathway inhibitors against certain cancers.

Figure 4.. Metabolic regulation of histone acetylation impacts phenotypes of both cancer cells and non-malignant cells in the tumors.

In addition to its direct roles in metabolism, acetyl-CoA is used for protein modification via acetylation. Nutrient-sensitive histone acetylation has been linked to regulation of gene expression in different cell types, potentially impacting tumor progression. In cancer cells, acetyl-CoA availability for histone acetylation has been linked to gene expression related to lipid metabolism, proliferation, and invasive properties. In macrophages, polarization towards the immune-suppressive M2 phenotype is ACLY-dependent. In T cells, production of IFNγ has been found to be responsive to acetyl-CoA production. The net effect of targeting acetyl-CoA metabolic enzymes may depend on effects in multiple cell types in the tumor microenvironment.