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G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells

Oncogene volume 25, pages 1955–1966 (2006)Cite this article

Abstract

Inhibition of telomerase activity by telomerase inhibitors induces a gradual loss of telomeres, and this in turn causes cancer cells to enter to a crisis stage. Here, we report the telomerase inhibitor telomestatin, which is known to stabilize G-quadruplex structures at 3′ single-stranded telomeric overhangs (G-tails), rapidly dissociates TRF2 from telomeres in cancer cells within a week, when given at a concentration that does not cause normal cells to die. The G-tails were dramatically reduced upon short-term treatment with the drug in cancer cell lines, but not in normal fibroblasts and epithelial cells. In addition, telomestatin also induced anaphase bridge formation in cancer cell lines. These effects of telomestatin were similar to those of dominant negative TRF2, which also causes a prompt loss of the telomeric G-tails and induces an anaphase bridge. These results indicate that telomestatin exerts its anticancer effect not only through inhibiting telomere elongation, but also by rapidly disrupting the capping function at the very ends of telomeres. Unlike conventional telomerase inhibitors that require long-term treatments, the G-quadruplex stabilizer telomestatin induced prompt cell death, and it was selectively effective in cancer cells. This study also identifies the TRF2 protein as a therapeutic target for treating many types of cancer which have the TRF2 protein at caps of the telomere DNA of each chromosome.

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Acknowledgements

This work was funded in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Dr Asako Nakamura for technical advise for telomere ChIP assay. We thank Angie M Sera not only for critical reading of the manuscript, but also for technical assistance.

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Authors and Affiliations

  1. Department of Cellular and Molecular Biology, Division of Integrated Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

    H Tahara, H Yamada & T Ide

  2. Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

    K Shin-ya

  3. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan

    H Seimiya & T Tsuruo

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  1. H Tahara
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  2. K Shin-ya
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  3. H Seimiya
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Correspondence to H Tahara or K Shin-ya.

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Tahara, H., Shin-ya, K., Seimiya, H. et al. G-Quadruplex stabilization by telomestatin induces TRF2 protein dissociation from telomeres and anaphase bridge formation accompanied by loss of the 3′ telomeric overhang in cancer cells. Oncogene 25, 1955–1966 (2006). https://doi.org/10.1038/sj.onc.1209217

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