Gabp Selectively Binds And Activates The Mutant Tert Promoter Across Multiple Cancer Types

Reactivation of telomerase reverse transcriptase (TERT) expression enables cells to overcome replicative senescence and escape apoptosis, fundamental steps in the initiation of human cancer. Multiple cancer types, including up to 83% of glioblastomas (GBM), harbor highly recurrent mutations in the TERT promoter specific to two nucleotide positions. The common mutation sites, G228A and G250A, may create de-novo ETS family transcription factor binding sites, but the precise mechanism of how these mutations confer increased TERT expression has been elusive. Here, we demonstrate the de-novo ETS motif to be critical for mutant TERT activation by site directed mutagenesis. A focused siRNA screen of the many ETS transcription factors expressed in GBM identifies GABPA as the single ETS factor to selectively regulate the mutant but not the wild type TERT promoter. Single molecule binding assays and ChIP-qPCR analysis reveal that GABPA is exclusively recruited to the mutant allele in vitro and in vivo respectively. Furthermore, this allelic recruitment is consistent across four tested cancer types, highlighting a shared mechanism underlying mutant TERT promoter activation. Tandem flanking native ETS motifs critically cooperate with these mutations to activate TERT, likely by facilitating GABP heterotetramer binding. GABP thus directly links TERT promoter mutations to aberrant expression and may provide a novel therapeutic target for multiple cancers. Citation Format: Robert J.A Bell, H. Tomas Rube, Alex Kreig, Andrew Mancini, Shaun F. Fouse, Raman P. Nagarajan, Serah Choi, Chibo Hong, Daniel He, Melike Pekmezci, John K. Wiencke, Margaret R. Wrensch, Susan M. Chang, Kyle M. Walsh, Sua Myong, Jun S. Song, Joseph F. Costello. GABP selectively binds and activates the mutant TERT promoter across multiple cancer types. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B12.