A research team from the University of Illinois at Urbana-Champaign and at the University of California, San Francisco says it has uncovered mechanisms by which common mutations result in elevated telomerase (TERT) expression. The team’s study (“The transcription factor GABP selectively binds and activates the mutant TERT promoter in cancer”), published in Science, has implications for new, more precise and personalized cancer treatments with fewer side effects compared with current treatments.
By integrating computational and experimental analyses, the researchers identified that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor that selectively binds the mutated sequences. Thus, the TERT mutations act as a new binding site for the transcription factor that controls TERT expression. The newly identified transcription factor does not recognize the normal TERT promoter sequence, and thus, does not regulate TERT in healthy tissue.
The team's work further showed that the same GABP (GA-binding protein) transcription factor recognizes and binds the mutant TERT promoter in tumor cells from four different cancer types, underscoring that this is a common mechanism of TERT reactivation.
“GABP directly links TERT promoter mutations to aberrant expression in multiple cancers,” wrote the investigators.
The identified transcription factor and its regulators have great potential for the development of new precision therapeutic interventions in cancers that harbor the TERT mutations, according to the scientists. A treatment that would inhibit TERT in a targeted cancer-cell-specific manner would bypass the toxicities associated with current treatments that inadvertently also target TERT in normal healthy cells.
Based on these new findings, the researchers are now conducting a variety of experiments designed to test whether inhibiting the transcription factor activity would not only turn down TERT expression, but might also result in selective cancer cell death.