BRAF-induced EHF Expression Affects TERT in Aggressive Papillary Thyroid Cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Papillary thyroid carcinoma (PTC) prognosis is synergistically affected by BRAFV600E and TERT promoter mutations.
• This interaction is thought to involve MAPK activation, leading to ETS transcription factor upregulation that targets the mutant TERT promoter.

Purpose of the Study:

• To investigate the role of ETS factors in PTC, focusing on their relationship with clinical features, BRAFV600E, and TERT promoter mutations.
• To elucidate the specific involvement of the ETS factor EHF in PTC progression and TERT regulation.

Main Methods:

• Analysis of transcriptomic data for 28 ETS factors in The Cancer Genome Atlas (TCGA) PTC cohort (n=399) and a local cohort (n=93).
• In vitro experiments, including overexpression and knockdown studies, to assess EHF's regulatory role in BRAFV600E and TERT expression.
• Chromatin immunoprecipitation (ChIP) and quantitative PCR (qPCR) to evaluate EHF binding to the TERT promoter.

Main Results:

• EHF was identified as a key ETS factor associated with adverse clinical features, BRAFV600E, and TERT promoter mutation/expression in both cohorts.
• High EHF expression correlated with shorter disease-free survival in BRAFV600E-mutated PTC.
• Concurrent BRAFV600E, TERT promoter mutations, and high EHF expression led to the poorest prognosis.
• EHF overexpression increased TERT expression in cells with concurrent BRAFV600E and TERT promoter mutations; BRAF inhibition reduced both EHF and TERT.
• ChIP-qPCR suggested EHF binds to the mutant TERT promoter.

Conclusions:

• The ETS transcription factor EHF is linked to poor prognosis in PTC.
• BRAF-V600E likely upregulates EHF, which subsequently enhances TERT expression in TERT promoter-mutated PTC cells.
• EHF represents a potential therapeutic target in PTC, especially in tumors with specific genetic alterations.