Dynamic telomerase gene suppression via network effects of GSK3 inhibition

Alan E. Bilsland, Stacey Hoare, Katrina Stevenson, Jane Plumb, Natividad Gomez-Roman, Claire Cairney, Sharon Burns, Kyle Lafferty-Whyte, Jon Roffey, Tim Hammonds, W. Nicol Keith

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

Abstract

Background: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective antitelomerase therapeutics and may reveal new targets to inhibit hTERT expression. Methodology/Principal Findings: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFkB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc. Conclusions/Significance: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting.

Original languageEnglish
Article numbere6459
Number of pages17
JournalPLoS ONE
Volume4
Issue number7
DOIs
Publication statusPublished - 31 Jul 2009

Keywords

  • GSK3 inhibition
  • telomerase
  • telomere homeostasis
  • telomerase inhibitors

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