Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression

Abstract

Cancer has been considered, for a long time, a genetic disease where mutations in keyregulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, theadvent of high-throughput technologies has revolutionized cancer research, allowing to investigatemolecular alterations at multiple levels, including genome, epigenome, transcriptome, proteome,and metabolome and showing the multifaceted aspects of this disease. The multi-omics approachesrevealed an intricate molecular landscape where different cellular functions are interconnected andcooperatively contribute to shaping the malignant phenotype. Recent evidence has brought to lighthow metabolism and epigenetics are highly intertwined, and their aberrant crosstalk can contributeto tumorigenesis. The oncogene-driven metabolic plasticity of tumor cells supports the energeticand anabolic demands of proliferative tumor programs and secondary can alter the epigeneticlandscape via modulating the production and/or the activity of epigenetic metabolites. Conversely,epigenetic mechanisms can regulate the expression of metabolic genes, thereby altering themetabolome, eliciting adaptive responses to rapidly changing environmental conditions, andsustaining malignant cell survival and progression in hostile niches. Thus, cancer cells takeadvantage of the epigenetics-metabolism crosstalk to acquire aggressive traits, promote cellproliferation, metastasis, and pluripotency, and shape tumor microenvironment. Understandingthis bidirectional relationship is crucial to identify potential novel molecular targets for theimplementation of robust anti-cancer therapeutic strategies.

Keywords: cancer; crosstalk; epigenetics; metabolism.

Figure 1

Most representative epigenetic chromatin modifications. The most representative epigenetic modifications on chromatin are histone acetylation and DNA/histone methylation. Epigenetic enzymes (writers or erasers) introduce or remove chemical tags, reversing chromatin shape from euchromatin to heterochromatin or vice versa, thus causing changes in gene expression. DNA methyltransferases [DNMTs] and Ten Eleven Translocation hydroxylases [TETs], respectively, add or remove the methyl groups on DNA. Histone methyltransferases [HMTs] and lysine demethylases [KDMs] are responsible for histone methylation/demethylation, whereas histone acetyltransferases [HATs] and deacetylases [HDACs] are the competitors for, respectively, addition or removal of acetyl groups at histone lysine residues.

Figure 2

Crosstalk between metabolism and epigenetics. Numerous metabolic intermediates contribute to epigenetic machinery as cofactors, like α-ketoglutarate [α-KG] for Ten Eleven Translocation hydroxylases [TETs] and Jumonji C domain-containing histone demethylases [JHDMs] activity, or as substrates, such as S-adenosyl-methionine [SAM] in DNA and histone methylation and acetyl-CoA [Ac-CoA] in histone acetylation. Moreover, metabolic reprogramming in cancer cells might promote the accumulation of particular metabolites, such as 2-hydroxyglutarate [2-HG], fumarate [FH], and succinate [SH], with tumorigenic driving effect due to their ability to interfere with epigenetic effectors. Nevertheless, epigenome alterations may influence cellular metabolism, controlling the expression of key metabolic enzymes involved in cancer metabolic reprogramming. DNMTs: DNA methyltransferases; HMTs: Histone methyltransferases; HATs: Histone acetyltransferases; HDACs: Histone deacetylases; TCA: Tricarboxylic acid; SAH: S-adenosyl homocysteine; PG: phosphoglycerate.

Figure 3

Direct and indirect epigenetic control of cellular metabolism. The DNA and histones methylation status influences the glycolytic flux through promoter hypermethylation or hypomethylation of enzymes with key-roles in the glycolytic pathway. Indeed, hypomethylation of PKM2 (pyruvate kinase embryonic isozyme M2) or HK2 (hexokinase 2) promoters is associated with the high glycolytic flow, whereas the downregulation of fructose 1,6-biphosphatase (FBP1) expression, due to promoter hypermethylation, inhibits gluconeogenesis and favors glycolytic metabolism. Moreover, epigenetic mechanisms indirectly control cell metabolism by promoter hypermethylation and consequent silencing of numerous tumor suppressor genes that repress PI3K/AKT/mTOR and HIF1α signaling pathways, two pro-tumorigenic cascades involved in prompting Warburg metabolism. Additionally, numerous histone demethylases, remodeling histone methylation patterns, influence cellular metabolism promoting transcriptional activation of several glycolytic genes, such as glucose transporter type 1 (GLUT1) and monocarboxylate transporter 4 (MCT4), as well as mediating the activity and/or availability of crucial transcription factors. Abbreviations: G6P-Glucose 6-Phosphate; F6P-Fructose 6-Phosphate; F1,6BP - Fructose 1,6-Biphosphate; DHAP Dihydroxyacetone Phosphate; G3P-Glyceraldehyde 3-Phosphate; 1,3BPG-1,3-Biphosphoglycerate; 3PG-3-Phosphoglycerate; 2PG-2-Phosphoglycerate; PEP-Phosphoenolpyruvate; TKRs-Tyrosine Kinase Receptors; PTEN-phosphatase and Tensin homolog; LKB1- Liver kinase B1; VHL-Von Hippel-Lindau tumor suppressor; PHD-Prolyl Hydroxylase Domain-containing protein.