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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.

plos computational biology/plos computational biology

Mathematical Model of a Telomerase Transcriptional Regulatory Network Developed by Cell-Based Screening: Analysis of Inhibitor Effects and Telomerase Expression Mechanisms