Associação Portuguesa de Investigação em Cancro
Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner
Disruption of the β1L Isoform of GABP Reverses Glioblastoma Replicative Immortality in a TERT Promoter Mutation-Dependent Manner
Authors and Affiliations:
Andrew Mancini,1,13 Ana Xavier-Magalhães,1,2,3,13 Wendy S. Woods,4 Kien-Thiet Nguyen,1 Alexandra M. Amen,1,5 Josie L. Hayes,1 Christof Fellmann,5 Michael Gapinske,4 Andrew M. McKinney,1 Chibo Hong,1 Lindsey E. Jones,1 Kyle M. Walsh,6 Robert J.A. Bell,1 Jennifer A. Doudna,5,7,8,9,10 Bruno M. Costa,2,3 Jun S. Song,11,12 Pablo Perez-Pinera,4,12 and Joseph F. Costello1,14,*
1Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
2Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
3ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimara ̃ es, 4710-057 Braga, Portugal
4Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
5Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
6Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, CA 94158, USA
7Department of Chemistry, University of California, Berkeley, CA 94720, USA
8Innovative Genomics Institute, University of California, Berkeley, CA 94720, USA
9MBIB Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
10Howard Hughes Medical Institute (HHMI), Berkeley, CA 94720, USA
11Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
12Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
13These authors contributed equally
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.
Journal: Cancer Cell
Link: https://www.ncbi.nlm.nih.gov/pubmed/30205050