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Epigenetic regulation of telomeres in human cancer

Oncogene volume 27, pages 6817–6833 (2008)Cite this article

Abstract

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.

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References

  • Bailey SM, Cornforth MN, Kurimasa A, Chen DJ, Goodwin EH . (2001). Strand-specific postreplicative processing of mammalian telomeres. Science 293: 2462–2465.

    Article  CAS  Google Scholar 

  • Bailey SM, Brenneman MA, Goodwin EH . (2004). Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells. Nucleic Acids Res 32: 3743–3751.

    Article  CAS  Google Scholar 

  • Bechter OE, Zou Y, Walker W, Wright WE, Shay JW . (2004). Telomeric recombination in mismatch repair deficient human colon cancer cells and telomerase inhibition. Cancer Res 64: 3444–3451.

    Article  CAS  Google Scholar 

  • Benetti R, Gonzalo S, Jaco I, Schotta G, Klatt P, Jenuwein T et al. (2007a). Suv4-20h deficiency results in telomere elongation and derepression of telomere recombination. J Cell Biol 178: 925–936.

    Article  CAS  Google Scholar 

  • Benetti R, García-Cao M, Blasco MA . (2007b). Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nat Genet 39: 243–350.

    Article  CAS  Google Scholar 

  • Blackburn EH . (2001). Switching and signaling at the telomere. Cell 106: 661–673.

    Article  CAS  Google Scholar 

  • Blasco MA . (2004). Carcinogenesis Young Investigator Award. Telomere epigenetics: a higher-order control of telomere length in mammalian cells. Carcinogenesis 25: 1083–1087.

    Article  CAS  Google Scholar 

  • Blasco MA . (2005). Telomeres and human disease: cancer, ageing and beyond. Nat Rev Genet 6: 611–622.

    Article  CAS  Google Scholar 

  • Blasco MA . (2007). The epigenetic regulation of mammalian telomeres. Nat Rev Genet 8: 299–309.

    Article  CAS  Google Scholar 

  • Canela A, Vera E, Klatt P, Blasco MA . (2007). High-throughput telomere length quantification by FISH and its application to human population studies. Proc Natl Acad Sci USA 104: 5300–5305.

    Article  CAS  Google Scholar 

  • Collins K, Mitchell JR . (2002). Telomerase in the human organism. Oncogene 21: 564–579.

    Article  CAS  Google Scholar 

  • De Lange T . (2005). Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19: 2100–2110.

    Article  CAS  Google Scholar 

  • Dunham MA, Neumann AA, Fasching CL, Reddel RR . (2000). Telomere maintenance by recombination in human cells. Nat Genet 26: 447–450.

    Article  CAS  Google Scholar 

  • Flores I, Benetti R, Blasco MA . (2006). Telomerase regulation and stem cell behaviour. Curr Opin Cell Biol 18: 254–260.

    Article  CAS  Google Scholar 

  • Fraga MF, Uriol E, Borja Diego L, Berdasco M, Esteller M, Canal MJ et al. (2002). High-performance capillary electrophoretic method for the quantification of 5-methyl 2′-deoxycytidine in genomic DNA: application to plant, animal and human cancer tissues. Electrophoresis 23: 1677–1681.

    Article  CAS  Google Scholar 

  • Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G et al. (2005). Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391–400.

    Article  CAS  Google Scholar 

  • Garcia-Aranda C, de Juan C, Diaz-Lopez A, Sanchez-Pernaute A, Torres AJ, Diaz-Rubio E et al. (2006). Correlations of telomere length, telomerase activity, and telomeric-repeat binding factor 1 expression in colorectal carcinoma. Cancer 106: 541–551.

    Article  CAS  Google Scholar 

  • García-Cao M, Gonzalo S, Dean D, Blasco MA . (2002). Role of the Rb family members in controlling telomere length. Nat Genet 32: 415–419.

    Article  Google Scholar 

  • García-Cao M, O’Sullivan R, Peters AH, Jenuwein T, Blasco MA . (2004). Epigenetic regulation of telomere length in mammalian cells by the Suv39h1 and Suv39h2 histone methyltransferases. Nat Genet 36: 94–99.

    Article  Google Scholar 

  • Gonzalo S, Blasco MA . (2005). Role of Rb family in the epigenetic definition of chromatin. Cell Cycle 4: 752–755.

    Article  CAS  Google Scholar 

  • Gonzalo S, García-Cao M, Fraga MF, Schotta G, Peters AHFM, Cotter SE et al. (2005). Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. Nat Cell Biol 7: 420–428.

    Article  CAS  Google Scholar 

  • Gonzalo S, Jaco I, Fraga MF, Chen T, Li E, Esteller M et al. (2006). DNA methyltransferases control telomere length and telomere recombination in mammalian cells. Nat Cell Biol 8: 416–424.

    Article  CAS  Google Scholar 

  • Guilleret I, Benhattar J . (2003). Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Exp Cell Res 289: 326–346.

    Article  CAS  Google Scholar 

  • Harley CB, Futcher AB, Greider CW . (1990). Telomeres shorten during ageing of human fibroblasts. Nature 345: 458–460.

    Article  CAS  Google Scholar 

  • Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB . (1996). Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826.

    Article  CAS  Google Scholar 

  • Kitagawa Y, Kyo S, Takakura M, Kanaya T, Koshida K, Namiki M et al. (2000). Demethylating reagent 5-azacytidine inhibits telomerase activity in human prostate cancer cells through transcriptional repression of hTERT. Clin Cancer Res 6: 2868–2875.

    CAS  PubMed  Google Scholar 

  • Kondo T, Bobek MP, Kuick R, Lamb B, Zhu X, Narayan A et al. (2000). Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2. Hum Mol Genet 9: 597–604.

    Article  CAS  Google Scholar 

  • Muntoni A, Reddel RR . (2005). The first molecular details of ALT in human tumor cells. Hum Mol Genet 14: 191–196.

    Article  Google Scholar 

  • Samper E, Goytisolo FA, Slijepcevic P, van Buul PP, Blasco MA . (2000). Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep 1: 244–252.

    Article  CAS  Google Scholar 

  • Shay JW, Wright WE . (2006). Telomerase therapeutics for cancer: challenges and new directions. Nat Rev Drug Discov 5: 577–584.

    Article  CAS  Google Scholar 

  • Steinert S, Shay JW, Wright WE . (2004). Modification of subtelomeric DNA. Mol Cell Biol 24: 4571–4580.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

EV is a predoctoral fellow of the Spanish Ministry of Education and Science (MEC). MA Blasco's Laboratory is funded by the MEC (SAF2005-00277, GEN2001-4856-C13-08), by the Regional Government of Madrid (GR/SAL/0597/2004), European Union (TELOSENS FIGH-CT-2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD FI6R-CT-2003-508842, MOL CANCER MED LSHC-CT-2004-502943) and the Josef Steiner Cancer Research Award 2003.

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Authors and Affiliations

  1. Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Center (CNIO), Madrid, Spain

    E Vera, A Canela & M A Blasco

  2. Cancer Epigenetics Group, Molecular Pathology Program, Spanish National Cancer Center (CNIO), Madrid, Spain

    M F Fraga & M Esteller

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  1. E Vera
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  2. A Canela
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  3. M F Fraga
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  4. M Esteller
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  5. M A Blasco
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Correspondence to M A Blasco.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Vera, E., Canela, A., Fraga, M. et al. Epigenetic regulation of telomeres in human cancer. Oncogene 27, 6817–6833 (2008). https://doi.org/10.1038/onc.2008.289

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