Epigenetics: Rewriting the ending
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Maintaining the length of telomeres is vital if rapidly dividing tumour cells are to attain immortality. Thus telomerase, which shows high levels of activity in 90% of tumours, is an important target for anticancer ther- apy. However, little is known about what other factors control telomere length, and how the other method of telomere elongation — alternative lengthening of telomeres (ALT) through homologous recombination — is activated in telomerase-negative tumours. Writing in Oncogene, Maria Blasco and colleagues illuminate the effects DNA methylation can have on telomere length. They used high- throughput, quantitative fluorescence in situ hybridization (FISH) in a var- ied panel of human cancer cell lines and non-transformed cells to meas- ure the average telomere length and the percentages of nuclei with very long (>6.5 kb) or very short (<2.5 kb) telomeres. As expected, telomerase activity positively correlated with telomere length. When they assessed global DNA methylation (by measur- ing the percentage of 5-methylcyto- sine residues) along with that at pericentromeric and subtelomeric repeat sequences (by sequencing of five specific repeats), they found a significant negative correlation between average telomere length and methylation at the two subtelomeric sites tested. This was not observed for global or pericentromeric methyla- tion, and there was no correlation between methylation of global DNA and that of subtelomeric DNA. Telomerase activity can be regu- lated by promoter methylation, so the authors investigated whether the relationship between telomere length and subtelomeric methylation was connected to this. However, no corre- lation was found between telomerase activity and DNA methylation, either globally or at the pericentric and sub- telomeric sites investigated. The other method of telomere elongation, ALT, was assessed by using chromosome- orientation FISH to determine the fre- quency of telomere sister chromatid exchange (T-SCE), which reflects the level of homologous recombination. Recombination was higher in tumour cell lines than in non-transformed cells, and increased T-SCE frequencies correlated with hypomethylation at subtelomeric repeat sequences and global DNA hypomethylation. T-SCE frequencies also correlated with telo- mere length, but not with telomerase activity, indicating that the elongated telomeres in these cells are generated by mechanisms other than activity of that enzyme. The authors went on to extend these results beyond the epithelial tumours represented by the cell lines tested, to lymphoid tumours. Interestingly, epithelial tumours showed lower levels of methylation at subtelomeres and higher fre- quencies of T-SCE than lymphoid tumours, indicating that epithelial tumours are more genetically unsta- ble. Furthermore, this instability, observed as T-SCE frequency, was increased by treatment with 5-aza- 2′-deoxycytidine, which is known to result in hypomethylation of subtelomeric repeats. The influence of subtelomeric hypomethylation on telomere length in cancer cells has important implications for cancer treatment: further knowledge of this alterna- tive pathway will be necessary to ensure the optimum design and use of telomerase inhibitors, and care must be taken in the use of hypomethylating drugs, which might in fact facilitate telomere lengthening and favour cancer growth. Finally, further understand- ing of the telomere-elongation mechanisms at work in telomerase- negative tumour cells could lead to therapies specifically targeting this process. Isobel Barry ORIGINAL RESEARCH PAPER Vera, E., Canela, A., Fraga, M. F., Esteller, M. & Blasco, M. A. Epigenetic regulation of telomeres in human cancer. Oncogene 1 Sep 2008 (doi:10.1038/ onc.2008.289) FURTHER READING Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nature Rev. Genet. 8, 299–309 (2007) EPIGENETICS Rewriting the ending STOCKBYTE RESEARCH HIGHLIGHTS NATURE REVIEWS | CANCER VOLUME 8 | OCTOBER 2008 Nature Reviews Cancer | AOP, published online 18 September 2008; doi:10.1038/nrc2512
Transcript of Epigenetics: Rewriting the ending
Maintaining the length of telomeres is vital if rapidly dividing tumour cells are to attain immortality. Thus telomerase, which shows high levels of activity in 90% of tumours, is an important target for anticancer ther-apy. However, little is known about what other factors control telomere length, and how the other method of telomere elongation — alternative lengthening of telomeres (ALT) through homologous recombination — is activated in telomerase-negative tumours.
Writing in Oncogene, Maria Blasco and colleagues illuminate the effects DNA methylation can have on telomere length. They used high-throughput, quantitative fluorescence in situ hybridization (FISH) in a var-ied panel of human cancer cell lines and non-transformed cells to meas-ure the average telomere length and the percentages of nuclei with very long (>6.5 kb) or very short (<2.5 kb) telomeres. As expected, telo merase activity positively correlated with
telomere length. When they assessed global DNA methylation (by measur-ing the percentage of 5-methylcyto-sine residues) along with that at pericentromeric and subtelomeric repeat sequences (by sequencing of five specific repeats), they found a significant negative correlation between average telomere length and methylation at the two subtelomeric sites tested. This was not observed for global or pericentromeric methyla-tion, and there was no correlation between methylation of global DNA and that of subtelomeric DNA.
Telomerase activity can be regu-lated by promoter methylation, so the authors investigated whether the relationship between telomere length and subtelomeric methylation was connected to this. However, no corre-lation was found between telomerase activity and DNA methylation, either globally or at the pericentric and sub-telomeric sites investigated. The other method of telomere elongation, ALT, was assessed by using chromosome-orientation FISH to determine the fre-quency of telomere sister chromatid exchange (T-SCE), which reflects the level of homologous recombination. Recombination was higher in tumour cell lines than in non-transformed cells, and increased T-SCE frequencies correlated with hypomethylation at subtelomeric repeat sequences and global DNA hypomethylation. T-SCE frequencies also correlated with telo-mere length, but not with telomerase activity, indicating that the elongated telomeres in these cells are generated by mechanisms other than activity of that enzyme.
The authors went on to extend these results beyond the epithelial tumours represented by the cell lines tested, to lymphoid tumours. Interestingly, epithelial tumours showed lower levels of methylation at subtelomeres and higher fre-quencies of T-SCE than lymphoid tumours, indicating that epithelial tumours are more genetically unsta-ble. Furthermore, this instability, observed as T-SCE frequency, was increased by treatment with 5-aza-2′-deoxycytidine, which is known to result in hypomethylation of subtelomeric repeats.
The influence of subtelomeric hypomethylation on telomere length in cancer cells has important implications for cancer treatment: further knowledge of this alterna-tive pathway will be necessary to ensure the optimum design and use of telomerase inhibitors, and care must be taken in the use of hypomethylating drugs, which might in fact facilitate telomere lengthening and favour cancer growth. Finally, further understand-ing of the telomere-elongation mechanisms at work in telomerase-negative tumour cells could lead to therapies specifically targeting this process.
Isobel Barry
ORIGINAL RESEARCH PAPER Vera, E., Canela, A., Fraga, M. F., Esteller, M. & Blasco, M. A. Epigenetic regulation of telomeres in human cancer. Oncogene 1 Sep 2008 (doi:10.1038/onc.2008.289)FuRtHER REAdING Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nature Rev. Genet. 8, 299–309 (2007)
E P I G E N E t I C S
Rewriting the ending
STOCKBYTE
R e s e a R c h h i g h l i g h t s
NATuRE REvIEWS | cancer voLuME 8 | oCToBER 2008
Nature Reviews Cancer | AoP, published online 18 September 2008; doi:10.1038/nrc2512
