Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Bilsland, A. E., Stevenson, K., Liu, Y., Hoare, S., Cairney, C. J., Roffey, J. and Keith, W. N. (2014) Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms. PLoS Computational Biology, 10(2), e1003448. (doi:10.1371/journal.pcbi.1003448) (PMID:24550717) (PMCID:PMC3923661)

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Abstract

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hoare, Miss Stacey and Bilsland, Dr Alan and Stevenson, Mrs Katrina and Cairney, Dr Claire and Keith, Professor Nicol and Liu, Dr Yu
Authors: Bilsland, A. E., Stevenson, K., Liu, Y., Hoare, S., Cairney, C. J., Roffey, J., and Keith, W. N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Computational Biology
Publisher:Public Library of Science
ISSN:1553-7358
ISSN (Online):1553-7358
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in PLoS Computational Biology 10(2):e1003448
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
551312Senectus: Exploitation of a Cell Senescence Drug Discovery ProgramNicol KeithCancer Research UK (CAN-RES-UK)C301/A12962RI CANCER SCIENCES
580721Optimisation of telomerase expression repressorsNicol KeithCancer Research UK (CAN-RES-UK)C301/A14762ICS - EXPERIMENTAL THERAPEUTICS