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Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Oncogene volume 31, pages 1–12 (2012)Cite this article

Abstract

Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells’ sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin–proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.

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Acknowledgements

This work is supported by grants from the Chinese NSFC (30901769), Guangdong National Science Foundation (9451008901002371) and the China Postdoctoral Science Foundation (20090450900) to B Zhang, and also partially by grants from the National Basic Research Program (973 program) of China (No. 2010CB912802) to H-F Kung and (No. 2010CB529404) to J-J Huang, the Chinese NSFC (30771074) to H Zhang.

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  1. B Zhang and D Qian: These authors contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China

    B Zhang, D Qian, M-Y Cai, Y-J Liao, H-X Deng, S-J Mai, Y-X Zeng, H-F Kung & D Xie

  2. Laboratory of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Beijing, China

    H-H Ma, R Jin, P-X Yang, H Zhang & J-J Huang

  3. Department of Pathology, Guangdong Provincial People's Hospital, Guangzhou, China

    Y-H Liu

  4. State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China

    M C Lin & H-F Kung

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  1. B Zhang
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Correspondence to H-F Kung, D Xie or J-J Huang.

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Zhang, B., Qian, D., Ma, HH. et al. Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation. Oncogene 31, 1–12 (2012). https://doi.org/10.1038/onc.2011.214

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