Epigenetic regulation in cancer

Abstract

Epigenetic modifications are defined as heritable changes in gene activity that do not involve changes in the underlying DNA sequence. The oncogenic process is driven by the accumulation of alterations that impact genome's structure and function. Genetic mutations, which directly disrupt the DNA sequence, are complemented by epigenetic modifications that modulate gene expression, thereby facilitating the acquisition of malignant characteristics. Principals among these epigenetic changes are shifts in DNA methylation and histone mark patterns, which promote tumor development and metastasis. Notably, the reversible nature of epigenetic alterations, as opposed to the permanence of genetic changes, positions the epigenetic machinery as a prime target in the discovery of novel therapeutics. Our review delves into the complexities of epigenetic regulation, exploring its profound effects on tumor initiation, metastatic behavior, metabolic pathways, and the tumor microenvironment. We place a particular emphasis on the dysregulation at each level of epigenetic modulation, including but not limited to, the aberrations in enzymes responsible for DNA methylation and histone modification, subunit loss or fusions in chromatin remodeling complexes, and the disturbances in higher-order chromatin structure. Finally, we also evaluate therapeutic approaches that leverage the growing understanding of chromatin dysregulation, offering new avenues for cancer treatment.

Keywords: cancer metastasis; epigenetics; tumor microenvironment; tumorigenesis.

FIGURE 1

Metabolic pathways and histone modification. Cells metabolize nutrients such as glucose, fatty acids, and amino acids, resulting in the production of various metabolites including acetyl‐coenzyme A (acetyl‐CoA), α‐ketoglutarate (α‐KG), succinate, S‐adenosylmethionine (SAM), and ATP. These metabolites serve as substrates or cofactors, essential in histone modification. Specifically, (1) pyruvate undergoes decarboxylation to generate acetyl‐CoA, whereas in hypoxic conditions, it is converted to lactate. Lactate produces lactyl‐CoA, which donates a lactyl group to lysine residues. (2) ATP‐citrate lyase (ACLY) catalyzes the transformation of citrate, derived from the tricarboxylic acid (TCA) cycle, into acetyl‐CoA, which undergoes acetylation when histone acetyltransferase (HAT) is present. (3) AMP‐activated protein kinase (AMPK) is necessary for the phosphorylation of histones based on the ratio of adenosine triphosphate (ATP) and adenosine monophosphate (AMP). (4) SAM is produced from methionine and is the donor of methyl groups for histone methylation reactions. Moreover, mutant isocitrate dehydrogenase (IDH) leads to the accumulation of oncometabolites 2‐hydroxyglutarate (2‐HG), succinate, and fumarate, which inhibit the demethylases histone demethylases (HDMs). (5) The primary substrate for succinylation is succinyl‐CoA, produced by the TCA cycle. HMT, histone methyltransferase; SAH, S‐adenosyl homocysteine.

FIGURE 2

Mechanism of key acetyl‐coenzyme A (acetyl‐CoA) metabolic enzymes in cancer metastasis. (A) Activated by protein kinase B (AKT) at S455, ATP‐citrate lyase (ACLY) inhibits ubiquitinated degradation of β‐catenin1 (CTNNB1) to promote epithelial–mesenchymal transition (EMT)‐related gene expression and generates acetyl‐CoA to stimulate dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1) by Ca2⁺ signals. (B) Acyl‐CoA synthetase short‐chain (ACSS)2‐derived acetyl‐CoA inhibits tumor metastasis by regulating acetylation of histone H3K27 and hypoxia‐inducible factor (HIF)‐2α. (C) Transforming growth factor β (TGF‐β) and leptin‐induced inactivation of acetyl‐CoA carboxylase (ACC) leads to the acetylation of Smad2, thereby promoting the upregulation of Snail and Slug. Ac, acetylation; ACOT12, acyl‐CoA thioesterase 12; AMPK, AMP‐activated protein kinase; CaN, calcineurin; LEF, lymphocyte enhancer factor; MMP, matrix metalloproteinase; OGT, O‐linked N‐acetylglucosamine transferase; P, phosphorylation; SIRT, silent information regulator; SREBPs, sterol regulatory element‐binding proteins; TAK, TGFβ‐activated kinase; Ub, ubiquitination.

FIGURE 3

Functional classification of chromatin remodeling complexes. (A) Switch/sucrose non‐fermentable (SWI/SNF) subfamily remodelers restructure chromatin via repositioning nucleosome or ejecting histone octamers. (B) Remodelers of the inositol requiring 80 (INO80) subfamily alter nucleosome composition by exchanging variant histones, as marked in purple. (C) Specific remodelers from the imitation SWI (ISWI) and chromodomain helicase DNA‐binding (CHD) subfamily are involved in nucleosome maturation and spacing.