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

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.

Analysis of the Cancer Genome Atlas Data to Determine the Prognostic Value of GABPB1L and TERT in Glioblastoma

“…Unlike previous study [7], we found a no association between TERT and GABPB1 expression. Recent study reported negative correlation between TERT and GABPB1 expression in grade III gliomas [12].…”

“…TERT promoter mutations produced novel binding motifs for E26 transformation-specific/ T-cell factor transcription factors, and increased transcriptional activity inducing telomere elongation [2,10]. Previous studies showed that TERT mutation generated a purine-rich GGAAG binding site for the transcription factor GA-binding protein of the ETS family and GABPB1L activated TERT promoter mutation [7,10,11]. It indicated these genetic changes were associated each other and it contributed to GBM progression.…”

“…Similar to many other E-twenty-six (ETS) factors, they also had oncogenic activities and were associated with the pathogenesis of leukemia, prostate cancer, and other malignancies [4][5][6]. Recent study introduced novel role of GABPB1L and telomerase reverse transcriptase (TERT) in GBM [7]. When combined with temozolomide chemotherapy, inducible GAB-PB1L knockdown and the associated TERT reduction led to an impaired DNA damage response that resulted in profoundly reduced growth of GBM tumor in vivo.…”

Mouse models of glioblastoma for the evaluation of novel therapeutic strategies

“… 106 , 107 Similarly, additional human GBM cell lines, such as LN229, LN18, and T98G have seen broad use in the literature. 108 Human GBM cell lines are easy to work with, can be maintained for extended periods of time in cell culture, and mimic human GBM histopathology. Given their similarity to human GBM, relative to other model types, they are frequently used to investigate tumor-specific signaling pathways such as intracellular growth systems, apoptosis signaling, and angiogenesis, as well as treatments targeting these pathways and mechanisms of treatment resistance.…”

Occurrence, functionality and abundance of the TERT promoter mutations

“…In a xenograft model, the decrease in tumor growth in the brains of immunocompromised mice ensued the implantation of human cells with disrupted GABPβ1L 152 . Combined with temozolomide chemotherapy, inducible GABPβ1L knockdown and associated TERT reduction reportedly affects DNA damage response leading to reduced growth of intracranial glioblastoma tumors 153 . Other ETS factors that bind those consensus sites on mutant alleles include ETS1 in glioblastoma and ETV5 in GABP‐negative cell lines from thyroid cancer 128,154 .…”