Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner

Cancer Cell. 2018 Sep 10;34(3):513-528.e8. doi: 10.1016/j.ccell.2018.08.003.

Abstract

TERT promoter mutations reactivate telomerase, allowing for indefinite telomere maintenance and enabling cellular immortalization. These mutations specifically recruit the multimeric ETS factor GABP, which can form two functionally independent transcription factor species: a dimer or a tetramer. We show that genetic disruption of GABPβ1L (β1L), a tetramer-forming isoform of GABP that is dispensable for normal development, results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting β1L culminates in telomere loss and cell death exclusively in TERT promoter mutant cells. Orthotopic xenografting of β1L-reduced, TERT promoter mutant glioblastoma cells rendered lower tumor burden and longer overall survival in mice. These results highlight the critical role of GABPβ1L in enabling immortality in TERT promoter mutant glioblastoma.

Keywords: GABP; TERT promoter mutation; cancer immortality; glioblastoma; telomerase; telomeres.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Female
  • GA-Binding Protein Transcription Factor / genetics
  • GA-Binding Protein Transcription Factor / metabolism*
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Glioblastoma / pathology*
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Mutation
  • Primary Cell Culture
  • Promoter Regions, Genetic / genetics*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Multimerization / genetics
  • RNA, Small Interfering / metabolism
  • Survival Analysis
  • Telomerase / genetics*
  • Telomerase / metabolism
  • Telomere / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • GA-Binding Protein Transcription Factor
  • GABPB1 protein, human
  • Protein Isoforms
  • RNA, Small Interfering
  • TERT protein, human
  • Telomerase