Csig-38. Reversal of Glioblastoma Replicative Immortality in a Tert Promoter Mutation-dependent Manner
Year: 2017
Type: article
Abstract: Hotspot mutations in the promoter region of the Telomerase Reverse Transcriptase (TERT) gene are the third most common recurrent mutation in cancer and occur in over 80% of IDH-wild type glioblastomas (GBMs). These single point mutations reactivate the telomerase complex, enabling cellular immortalization through the indefinite maintenance of telomere length. The transcription factor-binding site created by these point mutations specifically recruits the multimeric transcription factor GABP to the mutant TERT promoter. GABP is composed of the DNA-binding GABPα subunit and the trans-activating GABPβ subunit. GABP can form two transcription factor species – a dimer or a tetramer – depending on which of the structurally distinct GABPβ isoforms is incorporated into the complex. In this study, we show that depletion of the GABP tetramer-forming isoform GABPβ1L silences mutant TERT promoter in GBM cells. TERT promoter mutant cells lacking GABPβ1L fail to express TERT at levels sufficient for immortalization, thus leading to telomere shortening, DNA damage accumulation, and cell death in vitro. Additionally, mice bearing orthotopically xenografted TERT promoter mutant tumors lacking GABPβ1L had reduced tumor burden and prolonged survival in comparison to mice bearing GABPβ1L wild-type tumors. Importantly, loss of GABPβ1L has minimal phenotypic effects in a panel of TERT promoter wild-type cell lines, including a transformed human astrocyte line expressing TERT from its endogenous promoter. Exogenous expression of GABPB1L or TERT is sufficient to halt telomere degradation and loss of cell viability in GABPβ1L-deficient lines bearing the mutant TERT promoter. We have now begun to investigate upstream pathways that regulate GABP tetramer formation as well as co-factors required for GABP-mediated regulation of TERT as targets to reverse immortality in TERT promoter mutant GBM. Together, these results highlight the potentially widespread role of the GABP tetramer in enabling replicative immortality of TERT promoter mutant GBM.
Source: Neuro-Oncology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767909977