Cancer-specific loss of TERT activation sensitizes glioblastoma to DNA damage

Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase ( ) promoter. promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with reactivation a...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (13)
Main Authors: Amen, Alexandra M, Fellmann, Christof, Soczek, Katarzyna M, Ren, Shawn M, Lew, Rachel J, Knott, Gavin J, Park, Jesslyn E, McKinney, Andrew M, Mancini, Andrew, Doudna, Jennifer A, Costello, Joseph F
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents, Alkylating - pharmacology
Antineoplastic Agents, Alkylating - therapeutic use
Astrocytes
BASIC BIOLOGICAL SCIENCES
Biological Sciences
Brain Neoplasms - drug therapy
Brain Neoplasms - genetics
Brain Neoplasms - pathology
cancer
Cell Line, Tumor
Cell Proliferation - genetics
CRISPR
DNA Damage - drug effects
Drug Resistance, Neoplasm - genetics
Female
GA-Binding Protein Transcription Factor - genetics
GA-Binding Protein Transcription Factor - metabolism
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Gene Knockout Techniques
glioblastoma
Glioblastoma - drug therapy
Glioblastoma - genetics
Glioblastoma - pathology
HEK293 Cells
Humans
Mice
Mutation
Promoter Regions, Genetic - genetics
Protein Isoforms - metabolism
Telomerase - genetics
temozolomide
Temozolomide - pharmacology
TERT
Xenograft Model Antitumor Assays
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Summary:Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase ( ) promoter. promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform-containing complex to the mutant promoter. Furthermore, we find that promoter mutant GBM cells, unlike wild-type cells, exhibit a critical near-term dependence on GABPB1L for proliferation, notably also posttumor establishment in vivo. Up-regulation of the protein paralogue GABPB2, which is normally expressed at very low levels, can rescue this dependence. More importantly, when combined with frontline temozolomide (TMZ) chemotherapy, inducible GABPB1L knockdown and the associated reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of intracranial GBM tumors. Together, these findings provide insights into the mechanism of cancer-specific regulation, uncover rapid effects of GABPB1L-mediated suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for promoter mutant GBM.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2008772118