Causes and consequences of DNA hypomethylation in human cancer

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
... mehr
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.