Connections between metabolism and epigenetics in cancers

Abstract

In the past half century, our version on cancer, from tumor initiation, growth, to metastasis, is dominated by genetic mutation. The importance of metabolism and epigenetics was not recognized until most recently. Extensive cell proliferation is one of the hallmarks of cancers. To support the energetic and anabolic demands of enhanced proliferation, tumors reprogram the pathways of nutrient procurement and metabolism. In this context, a new link between metabolic alterations and cancer progression has been unraveled over the last decade by the studies conducted in the area of cancer cell metabolism. Cancer cells are known to alter their metabolic profile during the course of tumorigenesis and metastasis thereby exhibiting a tightly regulated program of metabolic plasticity. Noteworthy, certain metabolic alteration are known to occur at the epigenetic level, thus making epigenetics and metabolism highly interwoven in a reciprocal manner. Metabolites that are generated during metabolic pathways, such as in glycolytic cycle and oxidative phosphorylation, serve as cofactors or substrates for the enzymatic reactions that catalyze the epigenetic modifications and transcriptional regulation. Several studies also indicate that the epigenome is sensitive to cellular metabolism. Since many of the metabolic alterations and consequently aberrated epigenetic regulation are common to a wide range of cancer types, they serve as promising targets for anti-cancer therapies. Here we discuss the latest findings in cancer cell metabolism, elucidating the major anabolic, catabolic and energetic demands required for sustaining cancer growth, and the influence of altered metabolism on epigenetics and vice versa. A comprehensive research pertaining to metabolomic profiling and epigenome interactors/mediators in malignant neoplasias is imperative in deciphering the potential targets that can be exploited for the development of robust anti-cancer therapies.

Keywords: Cancer cell metabolism; DNA and histone methylation; Epigenetics; Warburg effect.

Figure 1. Signaling pathways regulating metabolism in cancer cells.

Network of several major anabolic and catabolic pathways results in energy production as well as generates protein, lipids and nucleotide biosynthesis through glycolysis, oxidative phosphorylation and pentose phosphate pathway. These metabolic pathways exert control over signaling via regulating reactive oxygen species (ROS), acetylation, and methylation. [PPP, pentose phosphate pathway; G6P, glucose-6-phosphate; 3-PG, 3-phosphoglycerate; ATP, adenosine 5´-triphosphate; mTORC1, mTOR complex 1; α-KG, α-ketoglutarate; RTK, receptor tyrosine kinase.] Image is adapted from [91].

Figure 2. Metabolites serves as cellular rheostats and regulate the epigenetic processes.

Variations in the concentration of several metabolites that act as either substrate or cofactors for key epigenetic enzymes, influence chromatin modification; also, by a feedback mechanism that dynamically regulates the entire process. (A) The tricarboxylic acid (TCA) generates metabolites that link energy pathways with epigenetic chromatin modifications, highlighted in orange. Glycolysis generates acetyl-CoA that feeds itself into the TCA cycle further and serves as a substrate for histone acetyltransferases (HATs). Pyruvate to acetyl-CoA conversion generates nicotinamide adenine dinucleotide (NAD+), which is needed by the sirtuin histone deacetylases (HDACs; histone deacetylation) and ADP-ribosyltransferases (ARTs). α-Ketoglutarate and Flavin adenine dinucleotide (FAD) serve as cofactors for DNA ten-eleven translocations (TETs) and histone demethylases (Jumonji C domain containing JmjC), LSD1. (B) Product metabolite SAdenosyl methionine (SAM) generated via one carbon cycle acts as a methyl donor to the histonemodifying enzymes, histone methyltransferases (HMT) & DNA methyltransferases (DNMT) thereby facilitating histone and DNA methylation. On the contrary, S-adenosylhomocysteine (SAH) negatively regulates this process, indicating that SAM/SAH ratio is essential in regulating DNA and histone methylation. (C) Cellular ATP/ADP ratio has a physiological role where conversion of adenosine triphosphate (ATP) to adenosine diphosphate (ADP) aids in anabolic process. Catabolism, however, relies on ADP to ATP conversion where activation of AMPactivated protein kinase (AMPK) is critical in regulating this balance. Therefore, within the cellular environment, NAD+ /NADH, Acetyl-CoA/Co-A, SAM/SAH, ATP/ADP ratio act as sensory signals (highlighted in green) governing the various epigenetic process.

Figure 3. Cellular metabolites contribute to gene regulation and their fluctuating levels affect the epigenetic process.

Addition or removal of epigenetic marks by several key epigenetic enzymes is dependent on metabolites that act as substrates or cofactors of these enzymes. [HAT, histone acetyltransferase enzymes; Ac, an acetyl mark; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; DNMT, DNA methyltransferase enzymes; HMT, histone methyltransferase enzymes; Me, a methyl mark; LSD1, lysine-specific histone demethylase 1; JHDM, Jumonji domain-containing histone demethylase enzymes; Cyt, cytosine; ^5meCyt, 5-methylcytosine; ^5hmCyt, 5-hydroxymethylcytosine; TET1/2, ten-eleven translocation methylcytosine dioxygenase 1/2; α-KG, α-ketoglutarate; SDH, succinate dehydrogenase; FH, fumarate hydratase; IDH1/2, isocitrate dehydrogenase 1/2]. Image is adapted from[92]