Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities

Abstract

Reversible, spatial, and temporal regulation of metabolic reprogramming and epigenetic homeostasis are prominent hallmarks of carcinogenesis. Cancer cells reprogram their metabolism to meet the high bioenergetic and biosynthetic demands for vigorous proliferation. Epigenetic dysregulation is a common feature of human cancers, which contributes to tumorigenesis and maintenance of the malignant phenotypes by regulating gene expression. The epigenome is sensitive to metabolic changes. Metabolism produces various metabolites that are substrates, cofactors, or inhibitors of epigenetic enzymes. Alterations in metabolic pathways and fluctuations in intermediate metabolites convey information regarding the intracellular metabolic status into the nucleus by modulating the activity of epigenetic enzymes and thus remodeling the epigenetic landscape, inducing transcriptional responses to heterogeneous metabolic requirements. Cancer metabolism is regulated by epigenetic machinery at both transcriptional and post-transcriptional levels. Epigenetic modifiers, chromatin remodelers and non-coding RNAs are integral contributors to the regulatory networks involved in cancer metabolism, facilitating malignant transformation. However, the significance of the close connection between metabolism and epigenetics in the context of cancer has not been fully deciphered. Thus, it will be constructive to summarize and update the emerging new evidence supporting this bidirectional crosstalk and deeply assess how the crosstalk between metabolic reprogramming and epigenetic abnormalities could be exploited to optimize treatment paradigms and establish new therapeutic options. In this review, we summarize the central mechanisms by which epigenetics and metabolism reciprocally modulate each other in cancer and elaborate upon and update the major contributions of the interplays between epigenetic aberrations and metabolic rewiring to cancer initiation and development. Finally, we highlight the potential therapeutic opportunities for hematological malignancies and solid tumors by targeting this epigenetic-metabolic circuit. In summary, we endeavored to depict the current understanding of the coordination between these fundamental abnormalities more comprehensively and provide new perspectives for utilizing metabolic and epigenetic targets for cancer treatment.

Keywords: RNA epigenetics; cancer; epigenetics; metabolic reprogramming; therapy.

FIGURE 1

Overview of the crosstalk between metabolic reprogramming and epigenetics in cancer. Metabolic reprogramming modulates epigenetics by providing substrates, cofactors, agonists, or antagonists for epigenetic modifiers and chromatin remodelers. The other way round, epigenetic mechanisms are involved in cancer metabolic reprogramming by regulating the expression and function of metabolic enzymes and upstream regulators

FIGURE 2

Metabolism pathways provide substrates and cofactors for epigenetic processes. Metabolic reprogramming is the hallmark of cancer. Cancer cells undergo a series of dramatic changes in cellular glucose, amino acids, and lipids metabolism to adapt to the external environment and meet the demands for rapid proliferation. Metabolites, such as acetyl‐CoA and SAM, generated from nutrients in these biochemical reactions provide acetyl groups and methyl groups for histone acetylation, histone methylation, DNA methylation, and RNA methylation. Besides, α‐KG and NAD⁺ are the cofactors of demethylases (TETs, JHDMs, ALKBH5, and FTO) and deacetylases (SIRTs). Oncometabolites that accumulate because of mutation or abnormal expression of metabolic enzymes are competitive inhibitors of many histone demethylases and the TET family of 5‐methylcytosine hydroxylases. Metabolic rewiring could change global metabolite levels and thus remodel the epigenome by modulating epigenetic modifiers. Abbreviations: Acetyl‐CoA, Acetyl‐coenzyme A; SAM, S‐adenosyl methionine; α‐KG, α‐ketoglutarate; NAD⁺, Nicotinamide adenine dinucleotide; TET, Ten‐eleven translocation family proteins; JHDM, Jumonji C domain‐containing histone demethylase; ALKBH5, AlkB homolog 5 RNA demethylase; FTO, Fat mass and obesity‐associated protein; SIRT, Sirtuin; NADH, Nicotinamide adenine dinucleotide; PHGDH, Phosphoglycerate dehydrogenase; PSAT1, Phosphoserine aminotransferase 1; PSPH, Phosphoserine phosphatase; 3‐PG, 3‐phosphoglycerate; 3PHP, 3‐phosphohydroxypyruvate; 3PS, 3‐phosphoserine; LDH, Lactate dehydrogenase; PDH, pyruvate dehydrogenase; ACL, ATP‐citrate lyase; ACSS2, Acetyl‐CoA synthetase 2; ACOT12, Acyl‐CoA thioesterase 12; IDH2, Isocitrate dehydrogenase 2; SDH, Succinate dehydrogenase; FDH, Fumarate dehydrogenase; D2HGDH, D2‐hydroxyglutarate dehydrogenase; MDH2, Malate dehydrogenase 2; mIDH2, Mutant isocitrate dehydrogenase 2; D2‐HG, D2‐hydroxyglutarate; L2HGDH, L2‐hydroxyglutarate dehydrogenase; L2‐HG, L2‐hydroxyglutarate; MDH1, Malate dehydrogenase 1; mIDH1, Mutant isocitrate dehydrogenase 2; IDH1, Isocitrate dehydrogenase 1; SHMT2, Serine hydroxymethyltransferase 2; SAH, S‐adenosyl homocysteine; MAT2A, Methionine adenosyltransferase 2A; NNMT, Nicotinamide N‐methyltransferase; NAM, Nicotinamide; 1MNA, 1‐methylnicotinamide; NAMPT, Nicotinamide phosphoribosyltransferase; SIRT1, Sirtuin 1; NMNAT1, Nicotinamide mononucleotide adenylyltransferase 1; NMN, Nicotinamide mononucleotide; HAT, Histone acetyltransferase; KMT, Histone lysine methyltransferase; HDAC, Histone deacetylase; KDM, Histone lysine demethylase; DNMT, DNA methyltransferase; METTL3, Methyltransferase‐like 3

FIGURE 3

Pattern diagrams of the mechanisms involved in regulating metabolism by lncRNAs and circRNAs. (A) LncRNAs can recruit DNA methyltransferase and histone acetyltransferase to the promoter region of metabolic enzyme genes. Altered DNA methylation and histone acetylation determine the transcriptional activation or repression of target genes. (B) LncRNAs can recruit transcription factors governing metabolism and promote gene transcription. (C) LncRNAs regulate alternative splicing and mRNA stability of metabolic enzymes and transcription factors. (D) LncRNAs can function as ceRNAs. LncRNAs sponge miRNAs and block miRNAs from binding with target mRNAs and suppressing the expression of enzymes, transcription factors, and upstream regulators. (E) LncRNAs can modulate the activity of metabolic enzymes and transcription factors by mediating their phosphorylation and can prevent them from ubiquitination and proteasome‐mediated degradation. (F) LncRNA can be a scaffold to promote phase separation and regulate the translation of metabolic enzymes. (G) CircRNAs can sponge miRNAs and antagonize the effect of miRNAs on metabolism. (H) CircRNAs can directly bind with mRNAs and affect their stability. (I) CircRNAs interact with proteins through different modes. CircRNAs can stabilize target proteins, mediate protein‐protein interactions and affect the binding of RNA‐binding proteins to mRNAs. Abbreviations: lncRNA, Long non‐coding RNA; ceRNA, Competing endogenous RNA; miRNA, MicroRNA; circRNA, Circular RNA