The immortality mechanism of TERT promoter mutant cancers is self-reinforcing and reversible

Nicholas O Stevers; Somang Kim; Jimmy Bo Yuan; Carter J Barger; Chibo Hong; Olivia Lenzo; Andrew M McKinney; Samuel H Wu; Yu Jin Lee; Darwin W Kwok; Abigail K Suwala; Christina L Appin; John D Gordan; Annette M Molinaro; Jun S Song; Joseph F Costello

doi:10.1016/j.molcel.2025.05.026

The immortality mechanism of TERT promoter mutant cancers is self-reinforcing and reversible

Mol Cell. 2025 Jun 19;85(12):2337-2354.e9. doi: 10.1016/j.molcel.2025.05.026. Epub 2025 Jun 12.

Authors

Affiliations

¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.
² Department of Physics, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Champaign, IL, USA.
³ Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Physics, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Institute for Genomic Biology, University of Illinois, Urbana-Champaign, Champaign, IL, USA; Cancer Center at Illinois, University of Illinois, Urbana-Champaign, Champaign, IL, USA. Electronic address: songj@illinois.edu.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA. Electronic address: joseph.costello@ucsf.edu.

PMID: 40513567
DOI: 10.1016/j.molcel.2025.05.026

Abstract

Activating mutations in the telomerase reverse transcriptase (TERT) promoter are prevalent in cancer and enable limitless cell division characteristic of immortal cells. Solving the immortality mechanism represents a major step toward selective reversal in cancer cells. TERT promoter (TERTp) mutations create a de novo E26 transformation-specific (ETS) transcription factor binding motif. Here, we analyzed 53 cell lines representing 16 cancer types and 6 recurrent TERTp mutations and found that the GA-binding protein (GABP) tetramer is responsible for promoter activation in all cases. Surprisingly, TERT expression is maintained after tetramer depletion. Further investigation revealed an underlying network of auto-suppression among the GABP subunits. Release from it drives TERT maintenance via upregulated GABP dimers or a paralogous tetramer. The GABPB1L tetramer is therefore a pan-cancer, pan-mutation activator of the mutant TERT promoter, but it is replaceable. Domains shared by the three GABP complexes, rather than solely the B1L tetramer, are mutation-specific vulnerabilities.

Keywords: GABP; TERT promoter mutation; noncoding mutation; pan-cancer; telomere; tumor immortality.

MeSH terms

Binding Sites
Cell Line, Tumor
Cell Transformation, Neoplastic* / genetics
Cell Transformation, Neoplastic* / pathology
GA-Binding Protein Transcription Factor* / genetics
GA-Binding Protein Transcription Factor* / metabolism
Gene Expression Regulation, Neoplastic
Humans
Mutation*
Neoplasms* / enzymology
Neoplasms* / genetics
Neoplasms* / pathology
Promoter Regions, Genetic*
Protein Multimerization
Telomerase* / genetics
Telomerase* / metabolism

Substances

Telomerase
TERT protein, human
GA-Binding Protein Transcription Factor
GABPB1 protein, human