Causes and consequences of DNA hypomethylation in human cancer

被引:177
作者
Hoffmann, MJ
Schulz, WA
机构
[1] Univ Dusseldorf, Dept Urol, D-40225 Dusseldorf, Germany
[2] Univ Dusseldorf, Ctr Biol & Med Res, D-40225 Dusseldorf, Germany
关键词
chromatin regulator proteins; retrotransposon; metastasis; chromosomal instability; methyltransferase; ectopic expression;
D O I
10.1139/o05-036
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
While specific genes are hypermethylated in the genome of cancer cells, overall methylcytosine content is often decreased as a consequence of hypomethylation affecting many repetitive sequences. Hypomethylation is also observed at a number of single-copy genes. While global hypomethylation is highly prevalent across all cancer types, it often displays considerable specificity with regard to tumor type, tumor stage, and sequences affected. Following an overview of hypomethylation alterations in various cancers, this review focuses on 3 hypotheses. First, hypomethylation at a single-copy gene may occur as a 2-step process, in which selection for gene function follows upon random hypomethylation. In this fashion, hypomethylation facilitates the adaptation of cancer cells to the ever-changing tumor tissue microenvironment, particularly during metastasis. Second, the development of global hypomethylation is intimately linked to chromatin restructuring and nuclear disorganization in cancer cells, reflected in a large number of changes in histone-modifying enzymes and other chromatin regulators. Third, DNA hypomethylation may occur at least partly as a consequence of cell cycle deregulation disturbing the coordination between DNA replication and activity of DNA methyltransferases. Finally, because of their relation to tumor progression and metastasis, DNA hypomethylation markers may be particularly useful to classify cancer and predict their clinical course.
引用
收藏
页码:296 / 321
页数:26
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