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Abstract
Alterations in the epigenome and metabolism affect molecular rewiring of cancer cells facilitating cancer development and progression. Modulation of histone and DNA modification enzymes occurs owing to metabolic reprogramming driven by oncogenes and expression of metabolism-associated genes is, in turn, epigenetically regulated, promoting the well-known metabolic reprogramming of cancer cells and, consequently, altering the metabolome. Thus, several malignant traits are supported by the interplay between metabolomics and epigenetics, promoting neoplastic transformation. In this review we emphasize the importance of tumour metabolites in the activity of most chromatin-modifying enzymes and implication in neoplastic transformation. Furthermore, candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer.
Highlights
Specialty section: This article was submitted to Epigenomics and Epigenetics, a section of the journal Frontiers in Genetics
Candidate targets deriving from metabolism of cancer cells and altered epigenetic factors is emphasized, focusing on compounds that counteract the epigenomic-metabolic interplay in cancer
Genetic [eg., Polycomb EZH2 (McCabe et al, 2012) and isocitrate dehydrogenase (IDH) (Yan et al, 2009) mutations], environmental [e.g., hypoxia (Thienpont et al, 2016) and inflammation (O’Keefe, 2016)], or metabolic [butyrate (O’Keefe, 2016), folate (Waterland and Jirtle, 2003), and vitamin C (Hore et al, 2016)] insults can induce overly restrictive or overly permissive epigenetic landscape that contributes to neoplastic transformation (Flavahan et al, 2017)
Summary
Cytosine methylation occurring in regions with high frequency of CpG sites (CpG islands), mostly residing at promoter regions, is strongly implicated in transcriptional silencing (Easwaran et al, 2014). The most widely recognized epigenetic disruption in human cancers is CpG island promoter hypermethylation-associated silencing of tumor suppressor genes such as CDKN2A, MLH1, BRCA1 and VHL, which has been identified as driver for lung, colorectal, breast and renal cancer progression (Jones and Baylin, 2007; Esteller, 2008). In clear cell renal cell carcinoma, absence of VHL expression, due to VHL mutation and/or promoter hypermethylation, leading to HIF-1α constitutive activation, was associated with increased glycolytic metabolism (Semenza, 2007). Both mutations and epimutations have been found in genes encoding for enzymes involved in establishment and/or removal of specific DNA methylation patterns (Plass et al, 2013)
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