Ehrlich Melanie
Human Genetics Program/SL31, Department of Biochemistry, Tulane Medical School, New Orleans, Louisiana, LA 70122, USA.
Oncogene. 2002 Aug 12;21(35):5400-13. doi: 10.1038/sj.onc.1205651.
Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.
癌症相关的DNA低甲基化与癌症相关的高甲基化一样普遍，但这两种表观遗传异常通常似乎会影响不同的DNA序列。一般来说，基因组中发生低甲基化的部分比高甲基化的部分更多。癌症中的基因组高甲基化最常出现在基因区域的CpG岛中。相比之下，在癌症中，高度和中度重复的DNA序列，包括异染色质DNA重复序列、分散的逆转座子和内源性逆转录病毒元件，都经常出现低甲基化。此外，独特序列，包括转录控制序列，也常常发生与癌症相关的低甲基化。癌症相关的DNA低甲基化的高频率、受影响序列的性质以及与DNA高甲基化缺乏关联，都与DNA低甲基化在癌症形成或肿瘤进展中的独立作用相一致。核型不稳定性增加以及通过顺式或反式效应激活促肿瘤基因，这可能包括改变异染色质-常染色质相互作用，可能是有利于肿瘤发生的DNA低甲基化的重要后果。鉴于涉及降低DNA甲基化的癌症治疗方法，考虑DNA低甲基化与肿瘤发生的关系非常重要。诱导DNA低甲基化可能具有短期抗癌作用，但也可能有助于加速经受DNA去甲基化化疗后存活的癌细胞的肿瘤进展。
