Dynamic telomerase gene suppression via network effects of GSK3 inhibition

Bilsland, A.E., Hoare, S.F., Stevenson, K.H., Plumb, J.A., Gomez-Roman, N. , Cairney, C.J., Burns, S., Lafferty-Whyte, K., Hammonds, T. and Keith, W.N. (2009) Dynamic telomerase gene suppression via network effects of GSK3 inhibition. PLoS ONE, 4(7), e6459. (doi: 10.1371/journal.pone.0006459)

Abstract

<b>Background</b>: 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 anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression. <b>Methodology/Principal Findings</b>: 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, NFκB, 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. <b>Conclusions/Significance</b>: 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Burns, Mrs Sharon and Hoare, Miss Stacey and Plumb, Dr Jane and Bilsland, Dr Alan and Stevenson, Mrs Katrina and Cairney, Dr Claire and Keith, Professor Nicol and Gomez-Roman, Dr Maria
• Authors: Bilsland, A.E., Hoare, S.F., Stevenson, K.H., Plumb, J.A., Gomez-Roman, N., Cairney, C.J., Burns, S., Lafferty-Whyte, K., Hammonds, T., and Keith, W.N.
• Subjects: Q Science > QH Natural history > QH426 Genetics; Q Science > QH Natural history > QH301 Biology
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 31 July 2009
• Copyright Holders: Copyright © 2009 The Authors
• First Published: First published in PLoS One 4(7):e6459
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher