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Telomerase directly regulates NF-κB-dependent transcription

Abstract

Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-κB, a master regulator of inflammation. We observe that while blocking NF-κB signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-κB activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-κB-dependent gene expression by binding to the NF-κB p65 subunit and recruitment to a subset of NF-κB promoters such as those of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression. As NF-κB can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers.

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Figure 1: Functional intersection between telomerase and NF-κB signalling.
Figure 2: Telomerase regulates NF-κB-dependent gene expression.
Figure 3: Telomerase-null mice exhibit defective NF-κB signalling.
Figure 4: Telomerase is recruited to selective NF-κB target gene promoters.
Figure 5: Reduction in the level of TNF-α-induced genome-wide p65 occupancy due to telomerase inhibition.
Figure 6: Enhanced NF-κB binding to the IL-6 promoter is dependent on telomerase.
Figure 7: Telomerase inhibition reduces expression of IL-6 in primary patient-derived leukaemia cells.

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References

  1. Blackburn, E. H. et al. Recognition and elongation of telomeres by telomerase. Genome 31, 553–560 (1989).

    Article  CAS  Google Scholar 

  2. Counter, C. M. et al. Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc. Natl Acad. Sci. USA 95, 14723–14728 (1998).

    Article  CAS  Google Scholar 

  3. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  Google Scholar 

  4. Verdun, R. E. & Karlseder, J. Replication and protection of telomeres. Nature 447, 924–931 (2007).

    Article  CAS  Google Scholar 

  5. Shay, J. W. & Wright, W. E. Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis 26, 867–874 (2005).

    Article  CAS  Google Scholar 

  6. Harley, C. B. Telomerase and cancer therapeutics. Nat. Rev. Cancer 8, 167–179 (2008).

    Article  CAS  Google Scholar 

  7. Chang, S. & DePinho, R. A. Telomerase extracurricular activities. Proc. Natl Acad. Sci. USA 99, 12520–12522 (2002).

    Article  CAS  Google Scholar 

  8. Gordon, D. M. & Santos, J. H. The emerging role of telomerase reverse transcriptase in mitochondrial DNA metabolism. J. Nucl. Acidshttp://dx.doi.org/10.4061/2010/390791 (2010).

  9. Maida, Y. et al. An RNA-dependent RNA polymerase formed by TERT and the RMRP RNA. Nature 461, 230–235 (2009).

    Article  CAS  Google Scholar 

  10. Martinez, P. & Blasco, M. A. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat. Rev. Cancer 11, 161–176 (2011).

    Article  CAS  Google Scholar 

  11. Sarin, K. Y. et al. Conditional telomerase induction causes proliferation of hair follicle stem cells. Nature 436, 1048–1052 (2005).

    Article  CAS  Google Scholar 

  12. Smith, L. L., Coller, H. A. & Roberts, J. M. Telomerase modulates expression of growth-controlling genes and enhances cell proliferation. Nat. Cell Biol. 5, 474–479 (2003).

    Article  CAS  Google Scholar 

  13. Stewart, S. A. et al. Telomerase contributes to tumorigenesis by a telomere length-independent mechanism. Proc. Natl Acad. Sci. USA 99, 12606–12611 (2002).

    Article  CAS  Google Scholar 

  14. Li, S., Crothers, J., Haqq, C. M. & Blackburn, E. H. Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA. J. Biol. Chem. 280, 23709–23717 (2005).

    Article  CAS  Google Scholar 

  15. Artandi, S. E. et al. Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc. Natl Acad. Sci. USA 99, 8191–8196 (2002).

    Article  CAS  Google Scholar 

  16. Blasco, M. A., Rizen, M., Greider, C. W. & Hanahan, D. Differential regulation of telomerase activity and telomerase RNA during multi-stage tumorigenesis. Nat. Genet. 12, 200–204 (1996).

    Article  CAS  Google Scholar 

  17. Cosme-Blanco, W. et al. Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53-dependent cellular senescence. EMBO Rep. 8, 497–503 (2007).

    Article  CAS  Google Scholar 

  18. Gonzalez-Suarez, E. et al. Increased epidermal tumors and increased skin wound healing in transgenic mice overexpressing the catalytic subunit of telomerase, mTERT, in basal keratinocytes. EMBO J. 20, 2619–2630 (2001).

    Article  CAS  Google Scholar 

  19. Gizard, F. et al. Telomerase activation in atherosclerosis and induction of telomerase reverse transcriptase expression by inflammatory stimuli in macrophages. Arterioscler Thromb. Vasc. Biol. 31, 245–252 (2011).

    Article  CAS  Google Scholar 

  20. Mitchell, J. R., Wood, E. & Collins, K. A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402, 551–555 (1999).

    Article  CAS  Google Scholar 

  21. Shkreli, M. et al. Reversible cell-cycle entry in adult kidney podocytes through regulated control of telomerase and Wnt signaling. Nature Med. 18, 111–119 (2011).

    Article  Google Scholar 

  22. Park, J. I. et al. Telomerase modulates Wnt signalling by association with target gene chromatin. Nature 460, 66–72 (2009).

    Article  CAS  Google Scholar 

  23. Indran, I. R., Hande, M. P. & Pervaiz, S. hTERT overexpression alleviates intracellular ROS production, improves mitochondrial function, and inhibits ROS-mediated apoptosis in cancer cells. Cancer Res. 71, 266–276 (2011).

    Article  CAS  Google Scholar 

  24. Mukherjee, S., Firpo, E. J., Wang, Y. & Roberts, J. M. Separation of telomerase functions by reverse genetics. Proc. Natl Acad. Sci. USA 108, E1363–E1371 (2011).

    Article  CAS  Google Scholar 

  25. Masutomi, K. et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc. Natl Acad. Sci. USA 102, 8222–8227 (2005).

    Article  CAS  Google Scholar 

  26. Joseph, I. et al. The telomerase inhibitor imetelstat depletes cancer stem cells in breast and pancreatic cancer cell lines. Cancer Res. 70, 9494–9504 (2010).

    Article  CAS  Google Scholar 

  27. Nitta, E. et al. Telomerase reverse transcriptase protects ATM-deficient hematopoietic stem cells from ROS-induced apoptosis through a telomere-independent mechanism. Blood 117, 4169–4180 (2011).

    Article  CAS  Google Scholar 

  28. Ren, J. G. et al. Expression of telomerase inhibits hydroxyl radical-induced apoptosis in normal telomerase negative human lung fibroblasts. FEBS Lett. 488, 133–138 (2001).

    Article  CAS  Google Scholar 

  29. Perkins, N. D. The diverse and complex roles of NF-κB subunits in cancer. Nat. Rev. Cancer 12, 121–132 (2012).

    Article  CAS  Google Scholar 

  30. Oeckinghaus, A., Hayden, M. S. & Ghosh, S. Crosstalk in NF-κB signaling pathways. Nature Immunol. 12, 695–708 (2011).

    Article  CAS  Google Scholar 

  31. Hayden, M. S. & Ghosh, S. Shared principles in NF-κB signaling. Cell 132, 344–362 (2008).

    Article  CAS  Google Scholar 

  32. Basseres, D. S., Ebbs, A., Levantini, E. & Baldwin, A. S. Requirement of the NF-κB subunit p65/RelA for K-Ras-induced lung tumorigenesis. Cancer Res. 70, 3537–3546 (2010).

    Article  CAS  Google Scholar 

  33. Loercher, A. et al. Nuclear factor-κB is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma. Cancer Res. 64, 6511–6523 (2004).

    Article  CAS  Google Scholar 

  34. DeNardo, D. G., Johansson, M. & Coussens, L. M. Inflaming gastrointestinal oncogenic programming. Cancer Cell 14, 7–9 (2008).

    Article  CAS  Google Scholar 

  35. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).

    Article  CAS  Google Scholar 

  36. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    Article  CAS  Google Scholar 

  37. Jones, R. L. et al. Nuclear NF-κB/p65 expression and response to neoadjuvant chemotherapy in breast cancer. J. Clin. Pathol. 64, 130–135 (2011).

    Article  Google Scholar 

  38. Teo, H. et al. Telomere-independent Rap1 is an IKK adaptor and regulates NF-κB-dependent gene expression. Nat. Cell Biol. 12, 758–767 (2010).

    Article  CAS  Google Scholar 

  39. Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nature Immunol. 12, 715–723 (2011).

    Article  CAS  Google Scholar 

  40. Wu, Z. H. et al. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol. Cell 40, 75–86 (2010).

    Article  CAS  Google Scholar 

  41. Perkins, N. D. Integrating cell-signalling pathways with NF-κB and IKK function. Nat. Rev. Mol. Cell Biol. 8, 49–62 (2007).

    Article  CAS  Google Scholar 

  42. Saccani, S., Marazzi, I., Beg, A. A. & Natoli, G. Degradation of promoter-bound p65/RelA is essential for the prompt termination of the nuclear factor κB response. J. Exp. Med. 200, 107–113 (2004).

    Article  CAS  Google Scholar 

  43. Chew, J. et al. WIP1 phosphatase is a negative regulator of NF-κB signalling. Nat. Cell Biol. 11, 659–666 (2009).

    Article  CAS  Google Scholar 

  44. Cabannes, E., Khan, G., Aillet, F., Jarrett, R. F. & Hay, R. T. Mutations in the IkBa gene in Hodgkin’s disease suggest a tumour suppressor role for IκBα. Oncogene 18, 3063–3070 (1999).

    Article  CAS  Google Scholar 

  45. Ngo, V. N. et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 470, 115–119 (2011).

    Article  CAS  Google Scholar 

  46. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).

    Article  CAS  Google Scholar 

  47. Van Antwerp, D. J., Martin, S. J., Kafri, T., Green, D. R. & Verma, I. M. Suppression of TNF- α-induced apoptosis by NF-κB. Science 274, 787–789 (1996).

    Article  CAS  Google Scholar 

  48. Seimiya, H. et al. Telomere shortening and growth inhibition of human cancer cells by novel synthetic telomerase inhibitors MST-312, MST-295, and MST-1991. Mol. Cancer Ther. 1, 657–665 (2002).

    CAS  PubMed  Google Scholar 

  49. Barkett, M. & Gilmore, T. D. Control of apoptosis by Rel/NF-κB transcription factors. Oncogene 18, 6910–6924 (1999).

    Article  CAS  Google Scholar 

  50. Pfeffer, K. et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    Article  CAS  Google Scholar 

  51. Dejager, L. & Libert, C. Tumor necrosis factor α mediates the lethalhepatotoxic effects of poly(I:C) in D-galactosamine-sensitized mice. Cytokine 42, 55–61 (2008).

    Article  CAS  Google Scholar 

  52. Yin, L., Hubbard, A. K. & Giardina, C. NF- κB regulates transcription of the mouse telomerase catalytic subunit. J. Biol. Chem. 275, 36671–36675 (2000).

    Article  CAS  Google Scholar 

  53. Vanden Berghe, W., De Bosscher, K., Boone, E., Plaisance, S. & Haegeman, G. The nuclear factor-κB engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter. J. Biol. Chem. 274, 32091–32098 (1999).

    Article  CAS  Google Scholar 

  54. Rentoukas, E. et al. Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome. PLoS One 7, e35739 (2012).

    Article  CAS  Google Scholar 

  55. Goytisolo, F. A. et al. Short telomeres result in organismal hypersensitivity to ionizing radiation in mammals. J. Exp. Med. 192, 1625–1636 (2000).

    Article  CAS  Google Scholar 

  56. Ping, L., Asai, A., Okada, A., Isobe, K. & Nakajima, H. Dramatic increase of telomerase activity during dendritic cell differentiation and maturation. J. Leukoc. Biol. 74, 270–276 (2003).

    Article  CAS  Google Scholar 

  57. Bodnar, A. G., Kim, N. W., Effros, R. B. & Chiu, C. P. Mechanism of telomerase induction during T cell activation. Exp. Cell Res. 228, 58–64 (1996).

    Article  CAS  Google Scholar 

  58. Ogoshi, M., Takashima, A. & Taylor, R. S. Mechanisms regulating telomerase activity in murine T cells. J. Immunol. 158, 622–628 (1997).

    CAS  PubMed  Google Scholar 

  59. Eaton, K. A., Opp, J. S., Gray, B. M., Bergin, I. L. & Young, V. B. Ulcerative typhlocolitis associated with Helicobacter mastomyrinus in telomerase-deficient mice. Vet. Pathol. 48, 713–725 (2011).

    Article  CAS  Google Scholar 

  60. Chu, C., Qu, K., Zhong, F. L., Artandi, S. E. & Chang, H. Y. Genomic maps of long noncoding RNA occupancy reveal principles of RNA-chromatin interactions. Mol. Cell 44, 667–678 (2011).

    Article  CAS  Google Scholar 

  61. Gilbert, L. A. & Hemann, M. T. DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355–366 (2010).

    Article  CAS  Google Scholar 

  62. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  Google Scholar 

  63. Li, S. et al. Rapid inhibition of cancer cell growth induced by lentiviral delivery and expression of mutant-template telomerase RNA and anti-telomerase short-interfering RNA. Cancer Res. 64, 4833–4840 (2004).

    Article  CAS  Google Scholar 

  64. Tergaonkar, V., Correa, R. G., Ikawa, M. & Verma, I. M. Distinct roles of IκB proteins in regulating constitutive NF-κB activity. Nat. Cell Biol. 7, 921–923 (2005).

    Article  CAS  Google Scholar 

  65. Fujita, P. A. et al. The UCSC Genome Browser database: update 2011. Nucleic Acids Res. 39, D876-882 (2011).

    Article  Google Scholar 

  66. Xu, H. et al. A signal-noise model for significance analysis of ChIP-seq with negative control. Bioinformatics 26, 1199–1204 (2010).

    Article  CAS  Google Scholar 

  67. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    Article  CAS  Google Scholar 

  68. Zhang, Z., Chang, C. W., Goh, W. L., Sung, W. K. & Cheung, E. CENTDIST: discovery of co-associated factors by motif distribution. Nucleic Acids Res. 39, W391–W399 (2011).

    Article  CAS  Google Scholar 

  69. Simonet, T. et al. The human TTAGGG repeat factors 1 and 2 bind to a subset of interstitial telomeric sequences and satellite repeats. Cell Res. 21, 1028–1038 (2011).

    Article  CAS  Google Scholar 

  70. McLean, C. Y. et al. GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Agency for Science Technology and Research, Singapore (A*Star) for funding and support to the V.T. laboratory.

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A.G., S.C.L., S.L., E.L. and V.T. designed experiments and planned the project. G.S., Z.Z., G.L. and W-K.S. carried our genome-wide analyses and were guided by E.L. A.G., E.M.S., E.K., S.C.L., M.W. and T.D.Y. carried out all experiments and animal work. J.Z. and W.J.C. provided patient samples and carried out experiments with patient material. A.G. and V.T. wrote the paper.

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Correspondence to Vinay Tergaonkar.

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Ghosh, A., Saginc, G., Leow, S. et al. Telomerase directly regulates NF-κB-dependent transcription. Nat Cell Biol 14, 1270–1281 (2012). https://doi.org/10.1038/ncb2621

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