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Regulation of replicative immortality by GABPβ1L in TERT promoter mutant glioblastoma

  • Author(s): Mancini, Andrew Guy
  • Advisor(s): Costello, Joseph F
  • et al.
Abstract

Telomeres are repetitive sequences of DNA that protect the ends of chromosomes and are gradually lost each cycle of cell division. In cells such as stem cells and germ cells, telomeres are indefinitely maintained through the use of the enzymatic complex telomerase. In order to achieve replicative immortality and form a tumor, cancer cells must find a way to replenish telomeres early on during tumorigenesis. The most common way that cancer cells enable immortality is by reactivating expression of the catalytic subunit, Telomerase Reverse Transcriptase (TERT), which is normally silenced in somatic cells. Activating mutations in the promoter region of TERT gene are the most common mechanism through which tumor cells 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 have identified GABPβ1L, the tetramer-forming isoform of GABP that is dispensable for normal development, as being specifically recruited to the mutant TERT promoter in glioblastoma cells. We show that genetic disruption of GABPβ1L results in TERT silencing in a TERT promoter mutation-dependent manner. Reducing TERT expression by disrupting GABPβ1L culminates in telomere loss and cell death through exclusively in TERT promoter mutant cells. Orthotopic xenografting of GABPβ1L-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.

TERT promoter mutations are the third most common mutation in human cancer, and the single most common mutation in glioblastoma. Understanding how the promoter mutation leads to tumor cell immortality could uncover potential targets to undermine immortality and reduce tumor growth. TERT promoter mutations selectively recruit the transcription factor GABP to activate TERT expression across multiple types of cancer. Our results suggest that the normally dispensable GABPβ1L isoform of GABP is a key to tumor cell immortality in TERT promoter mutant brain tumors. Therefore, inhibiting GABPβ1L may be an approach to reverse tumor cell immortality while sparing TERT promoter wild-type cells.

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