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Anthracyclines Disrupt Telomere Maintenance by Telomerase Through Inducing Pinx1 Ubiquitination and Degradation

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Anthracyclines Disrupt Telomere Maintenance by Telomerase Through Inducing Pinx1 Ubiquitination and Degradation Oncogene (2012) 31, 1–12 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc ORIGINAL ARTICLE Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation B Zhang1,5, D Qian1,5, H-H Ma2, R Jin2, P-X Yang2, M-Y Cai1, Y-H Liu3, Y-J Liao1, H-X Deng1, S-J Mai1, H Zhang2, Y-X Zeng1, MC Lin4, H-F Kung1,4, D Xie1 and J-J Huang2 1State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China; 2Laboratory of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Beijing, China; 3Department of Pathology, Guangdong Provincial People’s Hospital, Guangzhou, China and 4State Key Laboratory of Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China Telomere maintenance is essential for cancer growth. responsible for the hallmark immortalization phenotype Induction of telomere dysfunction, for example, by inhibition of cancer cells; this is because of its effect on telomere of telomeric proteins or telomerase, has been shown to maintenance. Consequently, targeting the pathway of strongly enhance cancer cells’ sensitivity to chemotherapies. telomere maintenance by telomerase represents a novel However, it is not clear whether modulations of telomere approach for anti-cancer therapy. Understanding how maintenance constitute cancer cellular responses to che- this carcinogenic pathway is regulated in cancer cells is motherapies. Furthermore, the manner in which anti-cancer highly desirable for this purpose. drugs affect telomere function remains unknown. In this Telomere is the terminal DNA component of the linear study, we show that anthracyclines, a class of anti-cancer chromosome. Owing to the incapacity of the DNA drugs widely used in clinical cancer treatments, have an active polymerase to fully replicate the very end sequences of role in triggering telomere dysfunction specifically in double-stranded chromosomes, telomeric DNA would telomerase-positive cancer cells. Anthracyclines interrupt shorten at a constant rate in each cell division (De Lange, telomere maintenance by telomerase through the down- 1998; Blackburn, 2000). When telomere shortens to a regulation of PinX1, a protein factor responsible for targeting critical point, it would trigger DNA-damage responses telomerase onto telomeres, thereby inhibiting telomerase (DDRs) at the chromosomal ends and force normal cells association with telomeres. We further demonstrate that into senescence. By contrast, telomerase, which is anthracyclines downregulate PinX1 by inducing this protein suppressed in normal somatic cells, is reactivated to degradation through the ubiquitin–proteasome-dependent counteract telomere shortening in nearly all human cancer pathway. Our data not only reveal a novel action for cells, and these malignant cells enjoy telomere-length anthracyclines as telomerase functional inhibitors but also maintenance and unlimited proliferative capacity (Kim provide a clue for the development of novel anti-cancer drugs et al., 1994; Autexier and Greider, 1996; Collins, 2000). based on telomerase/telomere targeting, which is actively Telomerase is a ribonucleoprotein reverse transcrip- investigated by many current studies. tase specialized for de novo synthesis of telomeric DNA Oncogene (2012) 31, 1–12; doi:10.1038/onc.2011.214; at chromosomal ends after each cell cycle. The core published online 6 June 2011 of this enzyme from all species is minimally composed of a protein-catalytic subunit and a single-stranded Keywords: anthracyclines; telomere dysfunction; PinX1; RNA called TERT and TR, respectively (Nugent and telomerase; cancer Lundblad, 1998; Collins, 2006). The expression of TERT has been demonstrated as a rate-limiting step in human cellular telomerase activation, and it is sup- pressed by multiple tumor-suppressor pathways in Introduction normal human cells but is activated by numerous oncogenic transcription factors (Meyerson et al., 1997; Telomerase reactivation has been identified as a key Liu et al., 2000; Cong et al., 2002; Lin and Elledge, 2003; step in human cellular tumorigenesis, and it is also Goueli and Janknecht, 2004). After its expression, regulations of the subcellular transportation of the Correspondence: Dr D Xie or Dr H-F Kung, State Key Laboratory of TERT protein contribute to telomere homeostasis Oncology in South China, Cancer Center, Sun Yat-Sen University, maintenance in telomerase-positive cancer cells. It has Room 634, 651, Dongfeng Road East, 510060 Guangzhou, China or Dr J-J Huang, Laboratory of Tumor and Molecular Biology, been shown that the expressed TERT undergoes a Beijing Institute of Biotechnology, 27, Taiping Road, Hai Dian highly programmed subcellular transportation before it District, Beijing 100850, China. reaches its final functional site at the telomere E-mail: [email protected] or (Wong et al., 2002; Tomlinson et al., 2006). Moreover, [email protected] or [email protected] 5These authors contributed equally to this work. regulations of the TERT subcellular transportation may Received 16 December 2010; revised and accepted 27 April 2011; have implications in the two central issues of telomerase/ published online 6 June 2011 telomere biology, that is, telomerase biogenesis and Anthracyclines disrupt telomere maintenance by telomerase B Zhang et al 2 telomerase telomere recruitment in vivo. Moreover, findings not only suggest that there is a PinX1-mediated alterations of TERT subcellular distributions have been pathway for telomere maintenance in cancer cells but observed in cancer cellular responses to certain cyto- they also indicate that the functional maintenance of toxic-damaging stimuli, such as DNA damages and this pathway may have an important impact on cancer oxidative stresses, emphasizing that modulations of cells’ survival under DNA-damaging stresses. Therefore, TERT transportation, thereby regulating the pathway it is worthwhile to further investigate whether modula- of telomere maintenance by telomerase, may have an tions of this pathway are involved in cancer cellular important impact on cancer cell survival under anti- responses to anti-cancer drug treatments. cancer treatments. However, how TERT transporta- Anthracyclines rank among the most-effective anti- tions are regulated in vivo is still poorly understood. cancer drugs ever developed. It has generally been Undoubtedly, elucidating these questions will facilitate accepted that anthracyclines function as a topoisome- the development of novel anti-cancer therapies based on rase poison and that they kill cancer cells through telomerase/telomere biology. inducing DNA double-stranded break (DSB) damage Telomere maintenance by telomerase requires telo- (Minotti et al., 2004). In this study, we show that the merase interplay with telomeric DNA. In cells, telomeric anthracyclines doxorubicin (DOX) and its analog DNA is coated with a set of specialized telomeric epirubicin (EPI) also have an effect on inducing proteins. Six telomere-constitutive protein components telomere dysfunction, specifically in telomerase-positive have been identified, including Pot1, TPP1, TIN2, cancer cells. We further demonstrate that both DOX TRF1, TRF2 and Rap1 (de Lange, 2005). These six and EPI perform this novel effect by triggering PinX1 telomeric proteins form a complex called shelterin at into a proteasome-dependent protein degradation path- telomere ends, and they function as a whole to protect way, thereby disrupting the telomere maintenance by telomeric DNA from being recognized as DNA broken telomerase in affected cancer cells. Therefore, we for the by the DNA damage-repair machinery but, meanwhile, first time provide the direct evidence that modulations of they also prevent telomerase from having access to its PinX1-dependent telomere maintenance by telomerase functional substrate telomeric DNA (de Lange, 2005; constitute cancer cellular responses to certain anti- Palm and de Lange, 2008). Therefore, communication cancer drug treatments, such as anthracyclines, and with the shelterin complex is an essential step for the that this may have important consequences for their telomerase to carry out its telomere maintenance action. anti-cancer effects. These novel findings may also Recent studies have revealed that in addition to provide a clue for designing new anti-cancer drugs participating in the shelterin formation, the Pot1-TPP1 based on targeting telomere maintenance by telomerase. heterodimers have crucial roles in recruiting telomerase function on telomeres (Xin et al., 2007). The studies suggest that the Pot1-TPP1 dimer may function as the Results telomerase receptor at telomeres for guiding this enzyme’s access to its functional default substrates. Inducible telomere dysfunction is specifically associated However, given that the Pot1-TPP1 dimer has been with anthracycline treatments in telomerase-positive considered as a constitutive telomeric component, how cancer cells the telomerase ribonucleoprotein complex, which is The induction of DNA DSB damage is a common clearly assembled within nuclei outside the telomere method for the action of most anti-cancer drugs to treat ends, is targetedly delivered onto the Pot1-TPP1 unit tumors. It has been shown that telomere maintenance still remains unknown. has great impact on cancer cellular responses to DSBs. The nucleolar protein PinX1 was originally found as Therefore, it is interesting to ask whether modulations an interacting protein of both the telomeric protein
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