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

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2008772118. doi: 10.1073/pnas.2008772118.

Abstract

Most glioblastomas (GBMs) achieve cellular immortality by acquiring a mutation in the telomerase reverse transcriptase (TERT) promoter. TERT promoter mutations create a binding site for a GA binding protein (GABP) transcription factor complex, whose assembly at the promoter is associated with TERT reactivation and telomere maintenance. Here, we demonstrate increased binding of a specific GABPB1L-isoform-containing complex to the mutant TERT promoter. Furthermore, we find that TERT 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 TERT 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 TERT regulation, uncover rapid effects of GABPB1L-mediated TERT suppression in GBM maintenance, and establish GABPB1L inhibition in combination with chemotherapy as a therapeutic strategy for TERT promoter mutant GBM.

Keywords: CRISPR; TERT; cancer; glioblastoma; temozolomide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Astrocytes
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • 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 / drug therapy
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation
  • Promoter Regions, Genetic / genetics
  • Protein Isoforms / metabolism
  • Telomerase / genetics*
  • Temozolomide / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • GA-Binding Protein Transcription Factor
  • GABPB1 protein, human
  • Protein Isoforms
  • TERT protein, human
  • Telomerase
  • Temozolomide