ETS Factor ETV5 Activates the Mutant Telomerase Reverse Transcriptase Promoter in Thyroid Cancer

Area of Science:

• Molecular Biology
• Cancer Genetics
• Transcription Factor Regulation

Background:

• Co-occurrence of TERT promoter (TERTp) mutations with BRAF/RAS mutations signifies aggressive thyroid cancer.
• TERTp mutations are hypothesized to create new binding sites for ETS transcription factors, activated by BRAF/RAS signaling.
• The specific ETS factors involved in TERTp activation may differ across cancer types.

Purpose of the Study:

• To identify the specific ETS transcription factor(s) responsible for TERT promoter activation in thyroid cancer.
• To elucidate the mechanism of TERT promoter activation by ETS factors in thyroid cancer.

Main Methods:

• In silico analysis of The Cancer Genome Atlas (TCGA) data.
• In vitro experiments using thyroid cancer cell lines.
• Quantitative reverse transcription-PCR, immunoprecipitation (IP), chromatin IP, and gene reporter assays.

Main Results:

• ETV5 was highly expressed in papillary thyroid cancers and thyroid cancer cell lines.
• ETV5 preferentially bound to the mutant TERTp allele (-124 bp(T)) and activated TERT transcription in GABP-deficient cells.
• ETV5 cooperates with FOXE1 to enhance mutant TERT promoter activity.

Conclusions:

• ETV5 is a key ETS factor that activates mutant TERT promoter in thyroid cancer.
• ETV5 exhibits mutant allele-specific binding to TERT promoter, a property previously attributed only to GABP.
• The cooperative action of ETV5 and FOXE1 in TERT activation may contribute to thyroid cancer risk associated with FOXE1 mutations.