Vera E, Canela A, Fraga M F, Esteller M, Blasco M A
Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain.
Oncogene. 2008 Nov 20;27(54):6817-33. doi: 10.1038/onc.2008.289. Epub 2008 Sep 1.
Hypomethylation of repeated elements in the genome is a common feature of human cancer, however, the direct consequences of this epigenetic defect for cancer biology are still largely unknown. Telomeres are specialized chromatin structures at the ends of eukaryotic chromosomes formed by tandem repeats of G-rich sequences and associated proteins, which have an essential role in chromosome end protection and genomic stability. Telomeric DNA repeats cannot be methylated, however, the adjacent subtelomeric DNA is heavily methylated in humans. Here, we show that the methylation status of subtelomeric DNA repeats negatively correlates with telomere length and telomere recombination in a large panel of human cancer cell lines. These findings suggest that tumor telomere length and integrity can be influenced by epigenetic factors. Finally, we show that treatment of human cancer cell lines with demethylating drugs results in hypomethylation of subtelomeric repeats and increased telomere recombination, which in turn may facilitate telomere elongation. All together, these findings suggest that tumor telomere length and integrity can be influenced by the epigenetic status of cancer cells.
基因组中重复元件的低甲基化是人类癌症的一个常见特征，然而，这种表观遗传缺陷对癌症生物学的直接影响在很大程度上仍然未知。端粒是真核染色体末端的特殊染色质结构，由富含G的序列和相关蛋白的串联重复组成，在染色体末端保护和基因组稳定性中起重要作用。端粒DNA重复序列不能被甲基化，然而，相邻的亚端粒DNA在人类中高度甲基化。在这里，我们表明，在一大组人类癌细胞系中，亚端粒DNA重复序列的甲基化状态与端粒长度和端粒重组呈负相关。这些发现表明，肿瘤端粒长度和完整性可能受表观遗传因素影响。最后，我们表明，用去甲基化药物处理人类癌细胞系会导致亚端粒重复序列低甲基化和端粒重组增加，这反过来可能促进端粒延长。总之，这些发现表明，肿瘤端粒长度和完整性可能受癌细胞表观遗传状态影响。
