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. 2004 Jun;45(1-2):23–32. doi: 10.1007/s10616-004-5122-4

Regulation of hTERT transcription: a target of cellular and viral mechanisms for immortalization and carcinogenesis

Izumi Horikawa 1,✉, Eriko Michishita 1, J Carl Barrett 1
PMCID: PMC3449964  PMID: 19003240

Abstract

A hallmark of human cancer cells is immortal cell growth, which is associated with telomere maintenance by telomerase. The transcriptional regulation of the human telomerase reverse transcriptase (hTERT) gene is a major mechanism that negatively and positively controls telomerase activity in normal and cancer cells, respectively. A growing body of data suggests that various cellular and viral factors and pathways involved in cell senescence, immortalization and carcinogenesis act on the hTERT promoter. The activity of the hTERT promoter is regulated, either directly or through signaling pathways, by oncogene products (e.g., Myc and Ets families) and tumor suppressor proteins (e.g., BRCA1). Endogenous factors involved in the physiological repression of the hTERT gene have also been revealed by chromosome transfer experiments. The integration of viral genomes in the hTERT locus can lead to hTERT activation and telomerase induction. Here, we summarize these findings and pay special attention to recent findings with relevance to the endogenous regulatory mechanisms of hTERT transcription.

Keywords: c-Myc, Human telomerase reverse transcriptase, Immortalization, Oncogenes, Telomerase, Transcriptional regulation, Tumor suppressor genes

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Glossary

ChIP

chromatin immunoprecipitation

HBV

hepatitis B virus

HIF

hypoxia-inducible factor

HPV

human papillomavirus

hTERT

human telomerase reverse transcriptase

MMCT

microcell-mediated chromosome transfer

RNAi

RNA interference

siRNA

small interfering RNA

TRRAP

transformation-transactivation domain-associated protein.

References

  1. Acker T., Plate K.H. A role for hypoxia and hypoxia-inducible transcription factors in tumor physiology. J. Mol. Med. 2002;80:562–575. doi: 10.1007/s00109-002-0355-1. [DOI] [PubMed] [Google Scholar]
  2. Aisner D.L., Wright W.E., Shay J.W. Telomerase regulation: not just flipping the switch. Curr. Opin. Genet. Dev. 2002;12:80–85. doi: 10.1016/S0959-437X(01)00268-4. [DOI] [PubMed] [Google Scholar]
  3. Akiyama M., Hideshima T., Hayashi T., Tai Y.T., Mitsiades C.S., Mitsiades N., Chauhan D., Richardson P., Munshi N.C., Anderson K.C. Cytokines modulate telomerase activity in a human multiple myeloma cell line. Cancer Res. 2002;62:3876–3882. [PubMed] [Google Scholar]
  4. Bryan T.M., Cech T.R. Telomerase and the maintenance of chromosome ends. Curr. Opin. Cell Biol. 1999;11:318–324. doi: 10.1016/S0955-0674(99)80043-X. [DOI] [PubMed] [Google Scholar]
  5. Campisi J., Kim S.H., Lim C.S., Rubio M. Cellular senescencecancer and aging: the telomere connection. Exp. Gerontol. 2001;36:1619–1637. doi: 10.1016/S0531-5565(01)00160-7. [DOI] [PubMed] [Google Scholar]
  6. Caplen N.J., Mousses S. Short interfering RNA (siRNA)-mediated RNA interference (RNAi) in human cells. Ann. NY Acad. Sci. 2003;1002:56–62. doi: 10.1196/annals.1281.007. [DOI] [PubMed] [Google Scholar]
  7. Cerezo A., Kalthoff H., Schuermann M., Schafer B., Boukamp P. Dual regulation of telomerase activity through c-Myc-dependent inhibition and alternative splicing of hTERT. J. Cell Sci. 2002;115:1305–1312. doi: 10.1242/jcs.115.6.1305. [DOI] [PubMed] [Google Scholar]
  8. Chen C.R., Kang Y., Massague J. Defective repression of c-myc in breast cancer cells: a loss at the core of the transforming growth factor beta growth arrest program. Proc. Natl. Acad. Sci. USA. 2001;98:992–999. doi: 10.1073/pnas.98.3.992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Devereux T.R., Horikawa I., Anna C.H., Annab L.A., Afshari C.A., Barrett J.C. DNA methylation analysis of the promoter region of the human telomerase reverse transcriptase (hTERT) gene. Cancer Res. 1999;59:6087–6090. [PubMed] [Google Scholar]
  10. Dimri G.P., Martinez J.L., Jacobs J.J., Keblusek P., Itahana K., Van Lohuizen M., Campisi J., Wazer D.E., Band V. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 2002;62:4736–4745. [PubMed] [Google Scholar]
  11. Ducrest A.L., Szutorisz H., Lingner J., Nabholz M. Regulation of the human telomerase reverse transcriptase gene. Oncogene. 2002;21:541–552. doi: 10.1038/sj.onc.1205081. [DOI] [PubMed] [Google Scholar]
  12. Ferber M.J., Montoya D.P., Yu C., Aderca I., McGee A., Thorland E.C., Nagorney D.M., Gostout B.S., Burgart L.J., Boix L., Bruix J., McMahon B.J., Cheung T.H., Chung T.K., Wong Y.F., Smith D.I., Roberts L.R. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003;22:3813–3820. doi: 10.1038/sj.onc.1206528. [DOI] [PubMed] [Google Scholar]
  13. Fernandez P.C., Frank S.R., Wang L., Schroeder M., Liu S., Greene J., Cocito A., Amati B. Genomic targets of the human c-Myc protein. Genes Dev. 2003;17:1115–1129. doi: 10.1101/gad.1067003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gewin L., Galloway D.A. E box-dependent activation of telomerase by human papillomavirus type 16 E6 does not require induction of c-myc. J. Virol. 2001;75:7198–7201. doi: 10.1128/JVI.75.15.7198-7201.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goueli B.S., Janknecht R. Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/NeuRas, or Raf. Mol. Cell. Biol. 2004;24:25–35. doi: 10.1128/MCB.24.1.25-35.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Greenberg R.A., O’Hagan R.C., Deng H., Xiao Q., Hann S.R., Adams R.R., Lichtsteiner S., Chin L., Morin G.B., DePinho R.A. Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation. Oncogene. 1999;18:1219–1226. doi: 10.1038/sj.onc.1202669. [DOI] [PubMed] [Google Scholar]
  17. Guilleret I., Benhattar J. Demethylation of the human telomerase catalytic subunit (hTERT) gene promoter reduced hTERT expression and telomerase activity and shortened telomeres. Exp. Cell Res. 2003;289:326–334. doi: 10.1016/S0014-4827(03)00281-7. [DOI] [PubMed] [Google Scholar]
  18. Günes C., Lichtsteiner S., Vasserot A.P., Englert C. Expression of the hTERT gene is regulated at the level of transcriptional initiation and repressed by Mad1. Cancer Res. 2000;60:2116–2121. [PubMed] [Google Scholar]
  19. Guo S.S., Sawicki M.P. Molecular and genetic mechanisms of tumorigenesis in multiple endocrine neoplasia type-1. Mol. Endocrinol. 2001;15:1653–1664. doi: 10.1210/me.15.10.1653. [DOI] [PubMed] [Google Scholar]
  20. Henning T., Kraus M., Brischwein M., Otto A.M., Wolf B. Relevance of tumor microenvironment for progression, therapy and drug development. Anticancer Drugs. 2004;15:7–14. doi: 10.1097/00001813-200401000-00002. [DOI] [PubMed] [Google Scholar]
  21. Horikawa I., Barrett J.C. cis-Activation of the human telomerase gene (hTERT) by the hepatitis B virus genome. J. Natl. Cancer Inst. 2001;93:1171–1173. doi: 10.1093/jnci/93.15.1171. [DOI] [PubMed] [Google Scholar]
  22. Horikawa I., Barrett J.C. Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis. 2003;24:1167–1176. doi: 10.1093/carcin/bgg085. [DOI] [PubMed] [Google Scholar]
  23. Horikawa I., Cable P.L., Afshari C., Barrett J.C. Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 1999;59:826–830. [PubMed] [Google Scholar]
  24. Horikawa I., Cable P.L., Mazur S.J., Appella E., Afshari C.A., Barrett J.C. Downstream E-box-mediated regulation of the human telomerase reverse transcriptase (hTERT) gene transcription: Evidence for an endogenous mechanism of transcriptional repression. Mol. Biol. Cell. 2002;13:2585–2597. doi: 10.1091/mbc.E01-11-0107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Hou M., Wang X., Popov N., Zhang A., Zhao X., Zhou R., Zetterberg A., Bjorkholm M., Henriksson M., Gruber A., Xu D. The histone deacetylase inhibitor trichostatin A derepresses the telomerase reverse transcriptase (hTERT) gene in human cells. Exp. Cell Res. 2002;274:25–34. doi: 10.1006/excr.2001.5462. [DOI] [PubMed] [Google Scholar]
  26. Jacobs J.J., Kieboom K., Marino S., DePinho R.A., van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature. 1999;397:164–168. doi: 10.1038/16476. [DOI] [PubMed] [Google Scholar]
  27. Jeon I.S., Davis J.N., Braun B.S., Sublett J.E., Roussel M.F., Denny C.T., Shapiro D.N. A variant Ewing’s sarcoma translocation (7;22) fuses the EWS gene to the ETS gene ETV1. Oncogene. 1995;10:1229–1234. [PubMed] [Google Scholar]
  28. Johnson K.D., Bresnick E.H. Dissecting long-range transcriptional mechanisms by chromatin immunoprecipitation. Methods. 2002;26:27–36. doi: 10.1016/S1046-2023(02)00005-1. [DOI] [PubMed] [Google Scholar]
  29. Kanaya T., Kyo S., Hamada K., Takakura M., Kitagawa Y., Harada H., Inoue M. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin. Cancer Res. 2000;6:1239–1247. [PubMed] [Google Scholar]
  30. Koshiji M., Kageyama Y., Pete E.A., Horikawa I., Barrett J.C., Huang L.E. HIF-1 α induces cell cycle arrest by functionally counteracting Myc. EMBO J. 2004;23:1949–1956. doi: 10.1038/sj.emboj.7600196. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Lee S.H., Kim J.W., Lee H.W., Cho Y.S., Oh S.H., Kim Y.J., Jung C.H., Zhang W., Lee J.H. Interferon regulatory factor-1 (IRF-1) is a mediator for interferon-gamma induced attenuation of telomerase activity and human telomerase reverse transcriptase (hTERT) expression. Oncogene. 2003;22:381–391. doi: 10.1038/sj.onc.1206133. [DOI] [PubMed] [Google Scholar]
  32. Leem S.H., Londoño-Vallejo J.A., Kim J.H., Bui H., Tubacher E., Solomon G., Park J.E., Horikawa I., Kouprina N., Barrett J.C., Larionov V. The human telomerase gene: complete genomic sequence and analysis of tandem repeat polymorphisms in intronic regions. Oncogene. 2002;21:769–777. doi: 10.1038/sj.onc.1205122. [DOI] [PubMed] [Google Scholar]
  33. Lessard J., Sauvageau G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature. 2003;423:255–260. doi: 10.1038/nature01572. [DOI] [PubMed] [Google Scholar]
  34. Li H., Lee T.H., Avraham H. A novel tricomplex of BRCA1, Nmiand c-Myc inhibits c-Myc-induced human telomerase reverse transcriptase gene (hTERT) promoter activity in breast cancer. J. Biol. Chem. 2002;277:20965–20973. doi: 10.1074/jbc.M112231200. [DOI] [PubMed] [Google Scholar]
  35. Lin S.Y., Elledge S.J. Multiple tumor suppressor pathways negatively regulate telomerase. Cell. 2003;113:881–889. doi: 10.1016/S0092-8674(03)00430-6. [DOI] [PubMed] [Google Scholar]
  36. Maida Y., Kyo S., Kanaya T., Wang Z., Yatabe N., Tanaka M., Nakamura M., Ohmichi M., Gotoh N., Murakami S., Inoue M. Direct activation of telomerase by EGF through Ets-mediated transactivation of TERT via MAP kinase signaling pathway. Oncogene. 2002;21:4071–4079. doi: 10.1038/sj.onc.1205509. [DOI] [PubMed] [Google Scholar]
  37. Makowski D.R., Rothberg P.G., Astrin S.M. The role of promoter insertion in the induction of neoplasia. Surv. Synth. Path. Res. 1984;3:342–349. doi: 10.1159/000156937. [DOI] [PubMed] [Google Scholar]
  38. Mathon N.F., Lloyd A.C. Cell senescence and cancer. Nat. Rev. Cancer. 2001;1:203–213. doi: 10.1038/35106045. [DOI] [PubMed] [Google Scholar]
  39. Meyerson M., Counter C.M., Eaton E.N., Ellisen L.W., Steiner P., Caddle S.D., Ziaugra L., Beijersbergen R.L., Davidoff M.J., Liu Q., Bacchetti S., Haber D.A., Weinberg R.A. hEST2, the putative human telomerase catalytic subunit geneis up-regulated in tumor cells and during immortalization. Cell. 1997;90:785–795. doi: 10.1016/s0092-8674(00)80538-3. [DOI] [PubMed] [Google Scholar]
  40. Nakamura T.M., Morin G.B., Chapman K.B., Weinrich S.L., Andrews W.H., Lingner J., Harley C.B., Cech T.R. Telomerase catalytic subunit homologs from fission yeast and human. Science. 1997;277:955–959. doi: 10.1126/science.277.5328.955. [DOI] [PubMed] [Google Scholar]
  41. Nikiforov M.A., Chandriani S., Park J., Kotenko I., Matheos D., Johnsson A., McMahon S.B., Cole M.D. TRRAP-dependent and TRRAP-independent transcriptional activation by Myc family oncoproteins. Mol. Cell Biol. 2002;22:5054–5063. doi: 10.1128/MCB.22.14.5054-5063.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Oh S., Song Y., Yim J., Kim T.K. The Wilms’ tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J. Biol. Chem. 1999;274:37473–37478. doi: 10.1074/jbc.274.52.37473. [DOI] [PubMed] [Google Scholar]
  43. Oshimura M., Barrett J.C. Multiple pathways to cellular senescence: role of telomerase repressors. Eur. J. Cancer. 1997;33:710–715. doi: 10.1016/S0959-8049(97)00090-7. [DOI] [PubMed] [Google Scholar]
  44. Park I.K., Qian D., Kiel M., Becker M.W., Pihalja M., Weissman I.L., Morrison S.J., Clarke M.F. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003;423:302–305. doi: 10.1038/nature01587. [DOI] [PubMed] [Google Scholar]
  45. Paterlini-Brechot P., Saigo K., Murakami Y., Chami M., Gozuacik D., Mugnier C., Lagorce D., Brechot C. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22:3911–3916. doi: 10.1038/sj.onc.1206492. [DOI] [PubMed] [Google Scholar]
  46. Poole J.C., Andrews L.G., Tollefsbol T.O. Activity, function, and gene regulation of the catalytic subunit of telomerase (hTERT) Gene. 2001;269:1–12. doi: 10.1016/S0378-1119(01)00440-1. [DOI] [PubMed] [Google Scholar]
  47. Ran Q., Pereira-Smith O.M. Genetic approaches to the study of replicative senescence. Exp. Gerontol. 2000;35:7–13. doi: 10.1016/S0531-5565(99)00080-7. [DOI] [PubMed] [Google Scholar]
  48. Shay J.W., Zou Y., Hiyama E., Wright W.E. Telomerase and cancer. Hum. Mol. Genet. 2001;10:677–685. doi: 10.1093/hmg/10.7.677. [DOI] [PubMed] [Google Scholar]
  49. Stampfer M.R., Garbe J., Nijjar T., Wigington D., Swisshelm K., Yaswen P. Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines. Oncogene. 2003;22:5238–5251. doi: 10.1038/sj.onc.1206667. [DOI] [PubMed] [Google Scholar]
  50. Takahashi A., Higashino F., Aoyagi M., Yoshida K., Itoh M., Kyo S., Ohno T., Taira T., Ariga H., Nakajima K., Hatta M., Kobayashi M., Sano H., Kohgo T., Shindoh M. EWS/ETS fusions activate telomerase in Ewing’s tumors. Cancer Res. 2003;63:8338–8344. [PubMed] [Google Scholar]
  51. Takakura M., Kyo S., Kanaya T., Hirano H., Takeda J., Yutsudo M., Inoue M. Cloning of human telomerase catalytic subunit (hTERT) gene promoter and identification of proximal core promoter sequences essential for transcriptional activation in immortalized and cancer cells. Cancer Res. 1999;59:551–557. [PubMed] [Google Scholar]
  52. Veldman T., Horikawa I., Barrett J.C., Schlegel R. Transcriptional activation of the telomerase hTERT gene by human papillomavirus type 16 E6 oncoprotein. J. Virol. 2001;75:4467–4472. doi: 10.1128/JVI.75.9.4467-4472.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Veldman T., Liu X., Yuan H., Schlegel R. Human papillomavirus E6 and Myc proteins associate in vivo and bind to and cooperatively activate the telomerase reverse transcriptase promoter. Proc. Natl. Acad. Sci. USA. 2003;100:8211–8216. doi: 10.1073/pnas.1435900100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Venkitaraman A.R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–182. doi: 10.1016/S0092-8674(02)00615-3. [DOI] [PubMed] [Google Scholar]
  55. Wang L., Soria J.C., Chang Y.S., Lee H.Y., Wei Q., Mao L. Association of a functional tandem repeats in the downstream of human telomerase gene and lung cancer. Oncogene. 2003;22:7123–7129. doi: 10.1038/sj.onc.1206852. [DOI] [PubMed] [Google Scholar]
  56. Wu K.J., Grandori C., Amacker M., Simon-Vermot N., Polack A., Lingner J., Dalla-Favera R. Direct activation of TERT transcription by c-MYC. Nat. Genet. 1999;21:220–224. doi: 10.1038/6010. [DOI] [PubMed] [Google Scholar]
  57. Xiao X., Athanasiou M., Sidorov I.A., Horikawa I., Cremona G., Blair D., Barrett J.C., Dimitrov D.S. Role of Ets/Id proteins for telomerase regulation in human cancer cells. Exp. Mol. Pathol. 2003;75:238–247. doi: 10.1016/S0014-4800(03)00092-3. [DOI] [PubMed] [Google Scholar]
  58. Xiong J., Fan S., Meng Q., Schramm L., Wang C., Bouzahza B., Zhou J., Zafonte B., Goldberg I.D., Haddad B.R., Pestell R.G., Rosen E.M. BRCA1 inhibition of telomerase activity in cultured cells. Mol. Cell. Biol. 2003;23:8668–8690. doi: 10.1128/MCB.23.23.8668-8690.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Xu D., Popov N., Hou M., Wang Q., Bjorkholm M., Gruber A., Menkel A.R., Hefnriksson M. Switch from Myc/Max to Mad1/Max binding and decrease in histone acetylation at the telomerase reverse transcriptase promoter during differentiation of HL60 cells. Proc. Natl. Acad. Sci. USA. 2001;98:3826–3831. doi: 10.1073/pnas.071043198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Xu D.W., Wang Q., Gruber A., Bjorkholm M., Chen Z.G., Zaid A., Selivanova G., Peterson C., Wiman K.G., Pisa P. Downregulation of telomerase reverse transcriptase mRNA expression by wild type p53 in human tumor cells. Oncogene. 2000;19:5123–5133. doi: 10.1038/sj.onc.1203890. [DOI] [PubMed] [Google Scholar]
  61. Yagi K., Furuhashi M., Aoki H., Goto D., Kuwano H., Sugamura K., Miyazono K., Kato M. c-myc is a downstream target of the Smad pathway. J. Biol. Chem. 2002;277:854–861. doi: 10.1074/jbc.M104170200. [DOI] [PubMed] [Google Scholar]
  62. Yang H., Kyo S., Takatura M., Sun L. Autocrine transforming growth factor beta suppresses telomerase activity and transcription of human telomerase reverse transcriptase in human cancer cells. Cell Growth Differ. 2001;12:119–127. [PubMed] [Google Scholar]
  63. Yang H., Ou C.C., Feldman R.I., Nicosia S.V., Kruk P.A., Cheng J.Q. Aurora-A kinase regulates telomerase activity through c-Myc in human ovarian and breast epithelial cells. Cancer Res. 2004;64:463–467. doi: 10.1158/0008-5472.can-03-2907. [DOI] [PubMed] [Google Scholar]
  64. Yatabe N., Kyo S., Maida Y., Nishi H., Nakamura M., Kanaya T., Tanaka M., Isaka K., Ogawa S., Inoue M. HIF-1-mediated activation of telomerase in cervical cancer cells. Oncogene. 2004;23:3708–3715. doi: 10.1038/sj.onc.1207460. [DOI] [PubMed] [Google Scholar]
  65. Yordy J.S., Muise-Helmericks R.C. Signal transduction and the Ets family of transcription factors. Oncogene. 2000;19:6503–6513. doi: 10.1038/sj.onc.1204036. [DOI] [PubMed] [Google Scholar]

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