title: The deep end of the metabolite pool: influences on epigenetic regulatory mechanisms in cancer.
abstract: BACKGROUND
  Epigenetic control of gene expression is mediated by cytosine methylation/demethylation and histone modifications including methylation, acetylation and glycosylation. The epigenetic programme is corrupted in cancer cells to maintain a pattern of gene expression that leads to their de-differentiated, rapidly proliferating phenotype. Enzymes responsible for modifying histones and cytosine are sensitive to the cellular metabolite pool and can be activated by an increase in their substrates or inhibited by an increase in their products or competitors for substrate binding.
  
  
  METHODS
  This review is based on publications identified on PubMed using a literature search of cytosine methylation, histone methylation, acetylation and glycosylation.
  
  
  RESULTS
  In cancer, changes in glycolytic enzymes lead to increased production of serine, increasing the pool of S-adenosylmethionine (the major methyl donor for methylation reactions) and UDP-N-acetylglucosamine (a substrate for O-linked glycosylation of histones and cytosine methyltransferases). Mutations in tricarboxylic acid cycle enzymes lead to accumulation of fumarate, succinate and hydroxyglutarate, all of which inhibit demethylation of cytosine and histones. In contrast, proline catabolism produces α-ketoglutarate and reactive oxygen, both of which promote the activity of enzymes that remove methyl groups from cytosine and histones, and the key enzyme in proline catabolism acts as a tumour suppressor.
  
  
  CONCLUSIONS
  Our emerging understanding of how the epigenetic profiles are metabolically reprogrammed in cancer cells will lead to novel diagnostic and therapeutic targets for treatment of patients.
authors.affiliation: Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
authors.forename: Kendra K
authors.initials: KK
authors.lastname: Nordgren
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Skildum
mesh_terms: D000107:Acetylation; D000117:Acetylglucosamine / Q000378:metabolism; D002952:Citric Acid Cycle; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006031:Glycosylation; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D009369:Neoplasms / Q000235:genetics*; D012436:S-Adenosylmethionine / Q000378:metabolism; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D006657:Histones; D014530:Uridine Diphosphate; D012436:S-Adenosylmethionine; D000117:Acetylglucosamine
keywords: Cancer; epigenetics; glycolysis; metabolism; n-acetylglucosamine; tricarboxylic acid cycle