Metabolic recoding of epigenetics in cancer

Metabolic recoding of epigenetics in cancer - PubMed

Review

Metabolic recoding of epigenetics in cancer

Yi-Ping Wang et al. Cancer Commun (Lond). 2018.

Abstract

Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. Recent advances in cancer metabolism shed light on how aberrations in metabolites and metabolic enzymes modify epigenetic programs. The metabolism-induced recoding of epigenetics in cancer depends strongly on nutrient availability for tumor cells. In this review, we focus on metabolic remodeling of epigenetics in cancer and examine potential mechanisms by which cancer cells integrate nutritional inputs into epigenetic modification.

Keywords: Cancer metabolism; Cancer microenvironment; DNA methylation; Epigenetics; Histone modification; Metabolites; Nutrient availability.

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Figures

**Fig. 1**
Cancer cells coordinate nutrient status with histone acetylation. Cancer cells alter histone acetylation in response to the availability of different carbon sources. *Ac-CoA* acetyl-CoA, *HAT* histone acetyltransferase, *HDAC* histone deacetylase, *SIRT* NAD⁺-dependent sirtuin family deacetylase, *NAM* nicotinamide

**Fig. 2**
Cancer cells coordinate nutrient status with the methylation of histone and DNA. Cancer cells alter methylation of histones (a) and DNA (b) in response to nutrient status. *SAM S*-adenosyl methionine, *SAH S*-adenyl homocysteine, *KMT* lysine methyltransferase, *PRMT* protein arginine methyltransferase, *LSD* lysine-specific demethylase, *DNMT* DNA methyltransferase, *TCA* tricarboxylic acid cycle, *TET* ten-eleven translocation methylcytosine dioxygenase

**Fig. 3**
Production of oncometabolites dysregulates epigenetics in cancer. Mutations in the metabolic enzymes IDH, FH, and SDH (red) promote the generation, respectively, of the oncometabolites 2-HG, fumarate, and succinate. Hypoxia causes LDH and MDH (grey) to produce 2-HG, which acts as a competitive inhibitor of α-KG-dependent dioxygenase to deregulate DNA and histone methylation. This leads to aberrant gene expression and cancer

**Fig. 4**
Metabolic recoding of epigenetics in cancer. a A model of random metabolic recoding of epigenetics in cancer. b Dose-dependent effect of metabolites on epigenetic enzymes. Higher accumulation of a specific metabolite affects more epigenetic targets. Half-maximal inhibitory concentrations (IC₅₀) of different target epigenetic enzymes are indicated as triangles. Different colors of triangles represent different epigenetic enzymes. c Metabolic enzymes translocate to the nucleus, where they bind to transcription factors that carry the enzymes to specific target sequences in the genome. d Nutrient sensing and signaling modulate the epigenetic machinery

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