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

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

Friday, 14.12.2018

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,
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