TERT promoter mutations and GABP transcription factors in carcinogenesis: More foes than friends

The transcriptional de-repression of the telomerase reverse transcriptase (TERT) gene and subsequent activation of telomerase is a prerequisite step in malignant transformation and progression. Recently, the gain-of-function mutation of the TERT promoter was identified in many types of human malignancies, and the mutated promoter acquires de novo ETS binding motifs through which the TERT transcription is activated. The ETS family transcription factors GABPA and GABPB1 have been shown to act as master drivers for the mutant TERT promoter activity. Indeed, GABPA or GABPB1 depletion leads to the down-regulation of TERT expression in the mutant TERT promoter-bearing cancer cells, and is thus proposed as targets for cancer therapy. Surprisingly, however, despite its key role in activating the mutant TERT promoter and telomerase, GABPA may itself function as a potent tumor suppressor in several malignancies. In this review, we address the collaboration between GABPA and mutant TERT promoter in cancer development, discuss selection trade-offs among different activities of GABPA in cancer evolution, and underscore the suppressive function of GABPA in cancer progression and implications in precision oncology.