Dynamic telomerase gene suppression via network effects of GSK3 inhibition.
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 anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression.


RESULTS
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, NFkappaB, 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
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.
Bilsland
Alan E
AE
Centre for Oncology and Applied Pharmacology, University of Glasgow, Cancer Research UK Beatson Laboratories, Garscube Estate, Bearsden, Glasgow, United Kingdom.
Hoare
Stacey
S
Stevenson
Katrina
K
Plumb
Jane
J
Gomez-Roman
Natividad
N
Cairney
Claire
C
Burns
Sharon
S
Lafferty-Whyte
Kyle
K
Roffey
Jon
J
Hammonds
Tim
T
Keith
W Nicol
WN
D000818:Animals; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D019098:Telomerase / Q000235:genetics*
D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; C509186:TERT protein, human; D019098:Telomerase