Metabolic reprogramming and epigenetic modifications on the path to cancer

Abstract

Metabolic rewiring and epigenetic remodeling, which are closely linked and reciprocally regulate each other, are among the well-known cancer hallmarks. Recent evidence suggests that many metabolites serve as substrates or cofactors of chromatin-modifying enzymes as a consequence of the translocation or spatial regionalization of enzymes or metabolites. Various metabolic alterations and epigenetic modifications also reportedly drive immune escape or impede immunosurveillance within certain contexts, playing important roles in tumor progression. In this review, we focus on how metabolic reprogramming of tumor cells and immune cells reshapes epigenetic alterations, in particular the acetylation and methylation of histone proteins and DNA. We also discuss other eminent metabolic modifications such as, succinylation, hydroxybutyrylation, and lactylation, and update the current advances in metabolism- and epigenetic modification-based therapeutic prospects in cancer.

Keywords: cancer therapy; epigenetics; metabolic reprogramming; tumor immunity; tumorigenesis.

Figure 1

Crosstalks between metabolic reprogramming, epigenetic modifications, and transcriptional regulation. The cell metabolome and epigenome interact in a two-way manner and with genetic and molecular drivers that regulate cancer. A comprehensive understanding of the interactions between molecular drivers, metabolic reprogramming, and epigenetic modifications in cancer will further elucidate their connections and contribute to the development of effective cancer therapies

Figure 2

An overview of metabolic connections to epigenetic remodeling. Nutrients such as glucose, fatty acids, and amino acids are metabolized by cells to produce a variety of metabolites, such as acetyl-CoA, NAD⁺, SAM, α-KG, ATP, and succinate, which function as substrates or cofactors to modify chromatin and proteins. Specifically, 1) UDP-GlcNAc, as a donor substrate derived from the HBP pathway integrating glucose, glutamine, fatty acid (acetyl-CoA), and nucleotide metabolism (UDP), is catalyzed by OGT for GlcNAcylation modification, and OGA controls the reverse reaction. 2) Lactate generates lactyl-CoA, which contributes a lactyl group to lysine residues of histone proteins through p300, generating a novel modification called lactylation. 3) Glucose-, fatty acid-, amino acid-, and acetate-derived acetyl-CoA are widely involved in acetylation modification. Histone acetylation is catalyzed by HATs, and the reverse reaction is mediated by lysine deacetylases (HDAC and SIRT). 4) Based on the ratio of ATP:AMP, AMPK is required for the phosphorylation of histones under various stress conditions. 5) Histone lysine β-hydroxybutyrylation (Kbhb) depends on the metabolite β-hydroxybutyrate (βOHB), which is produced by the ketone body metabolic pathway. The enzymes involved in acetylation modification mediate this reversible reaction. 6) Citrulline is categorized into two types: free citrulline from the arginine-coupled urea cycle and the guanidine dehydration of arginine residues on proteins to create citrulline residues. Histone citrullination is a PTM that converts arginine residues to citrulline via PAD enzymes, which are Ca²⁺-dependent. 7) TCA cycle-derived succinyl-CoA is the major substrate for succinylation, and the opposite reaction is mediated by KAT2A, CPT1A, and SIRT5. 8) Reversible chromatin methylation is coupled with SSP, the folate cycle, and the methionine cycle. SAM is the substrate for HMTs and DNMTs, leading to the production of SAH. Succinate, fumarate, and 2-HG inhibit the demethylases HDMs and TETs, which catalyze the demethylation reaction in an α-KG-dependent manner. In addition, NAD⁺ and NADH transitions are involved in modifications such as acetylation, β-hydroxybutyrylation, and succinylation

Figure 3

Compartmentalized acetyl-CoA metabolism in chromatin regulation. Under stimulation or stress conditions, mitochondrial-localized PDC and cytosol-localized ACLY and ACSS2 may translocate into the nucleus for the generation of the nuclear acetyl-CoA pool, mediating global histone acetylation (left). In certain cases, PDC binds with PKM2 and p300 to generate a large complex in the nucleus. In this large nuclear complex, the pyruvate kinase activity of PKM2 controls the production of pyruvate from PEP, and nuclear PDC further catalyzes the reaction in which pyruvate produces local acetyl-CoA to support the histone acetylation modification at special gene enhancers controlled by p300 (right)

Figure 4

Dietary-based approaches for cancer therapy. Genetic and environmental factors, including gene mutation, radiation, smoking, and excessive drinking, can cause a variety of human diseases, such as glioma, liver cancer, lung cancer, pancreatic cancer, kidney cancer, and colorectal cancer, which are associated with metabolic dysregulation and epigenetic remodeling. Dietary intake regulates nutrient availability, metabolite generation, and epigenetic modifications. Dietary changes in the composition of ketones (low carb, high fat diet, such as yogurt, eggs), glutamine (dietary fish, soybean), choline (dietary eggs, meat, fish), methionine (methionine restriction: dietary less proteins, it is only tested on animals), or serine (serine restriction: serine- and glycine-free diet, it is only tested on animals), may extend lifespan and have health-promoting effects by reshaping the homeostasis of metabolism and epigenetics such as methylation, acetylation, succinylation, and β-hydroxybutyrylation