DNA甲基化与癌症治疗。

DNA methylation and cancer therapy.

作者信息

Szyf Moshe

机构信息

Department of Pharmacology and Therapeutics, McGill University, 3655 Sir William Promenade, Quebec H3G 1Y6, Montreal, Canada.

出版信息

Drug Resist Updat. 2003 Dec;6(6):341-53. doi: 10.1016/j.drup.2003.10.002.

DOI:10.1016/j.drup.2003.10.002

PMID:14744498

Abstract

Vertebrate DNA is modified by methyl moieties at the 5'-position of cytosine rings residing in the di-nucleotide sequence CpG. Approximately 80% of CpG dinucleotide sequences are methylated. The pattern of distribution of methylated CGs is cell-type specific and correlates with gene expression programming and chromatin structure. Three kinds of seemingly contradictory aberrations in DNA methylation are observed in cancer, global hypomethylation, and regional hypermethylation and deregulated level of expression of DNA methyltransferases. It was previously proposed that the DNA methylation machinery is a candidate target for anticancer therapy. Inhibition of hypermethylation was the first therapeutic target. However, recent data suggests that inhibition of DNA methylation might have untoward effects such as induction of genes involved in metastasis. This review discusses the relative role of the three levels of alteration in the DNA methylation in cancer, proposes a unified hypothesis on the relative roles of increased DNA methyltransferase as well as the coexistence of hypo -and hyper- methylation in cancer and its possible implications on anticancer therapy.

摘要

脊椎动物的DNA在二核苷酸序列CpG中胞嘧啶环的5'位置被甲基基团修饰。大约80%的CpG二核苷酸序列被甲基化。甲基化的CG分布模式具有细胞类型特异性，并且与基因表达编程和染色质结构相关。在癌症中观察到三种看似矛盾的DNA甲基化异常：整体低甲基化、区域高甲基化以及DNA甲基转移酶表达水平失调。以前有人提出DNA甲基化机制是抗癌治疗的候选靶点。抑制高甲基化是第一个治疗靶点。然而，最近的数据表明抑制DNA甲基化可能会产生不良影响，如诱导参与转移的基因。这篇综述讨论了癌症中DNA甲基化三个改变水平的相对作用，提出了一个关于DNA甲基转移酶增加以及癌症中低甲基化和高甲基化共存的相对作用的统一假设及其对抗癌治疗的可能影响。