Compartmentation of Metabolites in Regulating Epigenomes of Cancer

Abstract

Covalent modifications of DNA and histones are important epigenetic events and the genomewide reshaping of epigenetic markers is common in cancer. Epigenetic markers are produced by enzymatic reactions, and some of these reactions require the presence of metabolites, specifically Epigenetic Enzyme Required Metabolites (EERMs), as cofactors. Recent studies found that the abundance of these EERMs correlates with epigenetic enzyme activities. Also, the subcellular compartmentation, especially the nuclear localization of these EERMs, may play a role in regulating the activities of epigenetic enzymes. Moreover, genespecific recruitment of enzymes that produce the EERMs in the proximity of the epigenetic modification events accompanying the regulation of gene expression, were proposed. Therefore, it is important to summarize findings of EERMs in regulating epigenetic modifications at both the DNA and histone levels, and to understand how EERMs contribute to cancer development by addressing their global versus local distribution.

Collagen Prolyl Hydroxylation–Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells

“…VitC, for instance, by enhancing the activity of the TET and JMJ demethylases, improves the efficiency of induced pluripotent stem cell (iPSC) generation (7)(8)(9)(10), drives embryonic stem cells (ESC) toward a naive state of pluripotency (11,12) and regulates the balance between self-renewal and differentiation of hematopoietic stem cells (13,14). Thus, fluctuation of EEMs' concentrations is considered an additional layer of epigenetic regulation (15). Yet, how this is regulated is still unknown.…”

The Mitochondrial Protein VDAC1 at the Crossroads of Cancer Cell Metabolism: The Epigenetic Link

“…Epigenetics refers to a change in chromatin that leads to the regulation of gene expression without alterations in the DNA sequence [6]. Epigenetic modifications include DNA methylation, and/or histone modifications by acetylation, ubiquitination, methylation, phosphorylation, sumoylation, glycosylation, and biotinylation, changes that play a critical role in many cellular processes [7][8][9][10][11][12][13]. The enzymes responsible for these modifications include histone acetyltransferases (HATs), histone deacetylases (HDACs), methyltransferases (KMTs), and demethylases (KDMs) [14][15][16].There is now an accumulation of evidence that the epigenome is sensitive to cellular metabolism and a link between metabolism and epigenetics [3][4][5][17][18][19] has been proposed, with epigenetics and gene transcription being influenced by products of metabolic pathways [20].…”

“…Methylation is linked to the intermediary metabolism through SAM, the primary source of methyl groups generated in the folate and methionine cycles, coupled to serine-derived one-carbon metabolism [27][28][29]. The activities of both histone methyltransferases (HMT) and DNA methyltransferases (DNMT) depend on intracellular SAM levels, which vary according to the nutrient availability of serine and methionine.Interplay between metabolism and epigenetics [4,5,[7][8][9]12,13,[17][18][19]30] is now considered an enabling characteristic of cancer [4,31,32]. Analysis of cancer samples revealed genome-wide epigenetic alterations that potentially regulate gene expression and are associated with tumor progression [33].…”

“…Interplay between metabolism and epigenetics [4,5,[7][8][9]12,13,[17][18][19]30] is now considered an enabling characteristic of cancer [4,31,32]. Analysis of cancer samples revealed genome-wide epigenetic alterations that potentially regulate gene expression and are associated with tumor progression [33].…”

Genome-wide methylome and chromatin interactome identify abnormal enhancer to be risk factor of breast cancer

“…Genome-wide demethylation of DNA is frequently observed in tumors and associated with genome instability [ 22 ]. But hypermethylated tumor suppressor promoters is also very common in tumors, suggesting there are independent mechanisms to regulate the global DNA methylation versus the gene-specific DNA methylation [ 23 ]. DNA methylation contributes to gene silencing involving many closely positioned CpG sites around the gene promoter.…”