More than 500,000 people in the United States die each year of cancer-related causes and a new study has identified the mechanism behind one of the most common mutations that help cancer cells replicate limitlessly.
Approximately 85 percent of cancer cells obtain their limitless replicative potential through the reactivation of a specific protein called telomerase (TERT). Recent cancer research has shown that highly recurrent mutations in the promoter of the TERT gene are the most common genetic mutations in many cancers, including adult glioblastoma and hepatocellular carcinoma.
TERT stabilizes chromosomes by elongating the protective element at the end of each chromosome in a cell. Scientists have discovered that cells harboring these mutations aberrantly increase TERT expression, effectively making them immortal.
Researchers have uncovered the mechanisms by which these common mutations result in elevated TERT expression by using computational and experimental analyses to determine that the mechanism of increased TERT expression in tumor tissue relies on a specific transcription factor - a protein that binds specific DNA sequences and regulates how its target genes are expressed - that selectively binds the mutated sequences.
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 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.
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. 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.