Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

Proc Natl Acad Sci U S A. 2021 Mar 16;118(11):e2022779118. doi: 10.1073/pnas.2022779118.

Abstract

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) TERT cascade plays a critical role in the regulation of mutant TERT, in which FOS acts as a transcriptional factor for GABPB to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type TERT promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant TERT cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type TERT cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) and inactivation of survivin, two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of survivin, up-regulating its expression. Thus, this study identifies a therapeutic strategy for TERT promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) TERT cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.

Keywords: FOS; TERT promoter mutation; TRAIL-R2; apoptosis; survivin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis / drug effects*
  • Benzophenones / pharmacology
  • Benzophenones / therapeutic use
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use
  • Mutation
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-fos / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Signal Transduction / drug effects
  • Survivin / genetics*
  • Survivin / metabolism
  • Telomerase / genetics*
  • Telomerase / metabolism

Substances

  • 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid
  • BIRC5 protein, human
  • Benzophenones
  • GA-Binding Protein Transcription Factor
  • GABPB1 protein, human
  • Isoxazoles
  • Proto-Oncogene Proteins c-fos
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Survivin
  • TNFRSF10B protein, human
  • TERT protein, human
  • Telomerase