Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN, USA.
Eur J Clin Invest. 2015 Jan;45 Suppl 1:9-15. doi: 10.1111/eci.12361.
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.
This review is based on publications identified on PubMed using a literature search of cytosine methylation, histone methylation, acetylation and glycosylation.
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.
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.
基因表达的表观遗传控制是由胞嘧啶甲基化/去甲基化和组蛋白修饰介导的，包括甲基化、乙酰化和糖基化。表观遗传程序在癌细胞中被破坏，以维持导致其去分化、快速增殖表型的基因表达模式。负责修饰组蛋白和胞嘧啶的酶对细胞代谢物池敏感，可以通过增加其底物来激活，也可以通过增加其产物或底物结合的竞争物来抑制。
这篇综述基于在 PubMed 上使用胞嘧啶甲基化、组蛋白甲基化、乙酰化和糖基化的文献搜索确定的出版物。
在癌症中，糖酵解酶的变化导致丝氨酸产量增加，增加 S-腺苷甲硫氨酸（甲基化反应的主要甲基供体）和 UDP-N-乙酰葡萄糖胺（组蛋白和胞嘧啶甲基转移酶的 O-连接糖基化的底物）的池。三羧酸循环酶的突变导致富马酸、琥珀酸和羟基戊二酸的积累，所有这些都抑制胞嘧啶和组蛋白的去甲基化。相比之下，脯氨酸分解代谢产生α-酮戊二酸和活性氧，两者都促进从胞嘧啶和组蛋白中去除甲基的酶的活性，脯氨酸分解代谢的关键酶作为肿瘤抑制因子。
我们对癌细胞中表观遗传谱如何被代谢重新编程的认识不断加深，将为治疗患者带来新的诊断和治疗靶点。
