Abstract
BackgroundAlthough FOXE1 was initially recognized for its role in thyroid organogenesis, more recently a strong association has been identified between the FOXE1 locus and thyroid cancer. The role of FOXE1 in adult thyroid, and in particular regarding cancer risk, has not been well established. We hypothesised that discovering key FOXE1 transcriptional partners would in turn identify regulatory pathways relevant to its role in oncogenesis.ResultsIn a transcription factor-binding array, ELK1 was identified to bind FOXE1. We confirmed this physical association in heterologously transfected cells by IP and mammalian two-hybrid assays. In thyroid tissue, endogenous FOXE1 was shown to bind ELK1, and using ChIP assays these factors bound thyroid-relevant gene promoters TPO and TERT in close proximity to each other. Using a combination of electromobility shift assays, TERT promoter assays and siRNA-silencing, we found that FOXE1 positively regulated TERT expression in a manner dependent upon its association with ELK1. Treating heterologously transfected thyroid cells with MEK inhibitor U0126 inhibited FOXE1-ELK1 interaction, and reduced TERT and TPO promoter activity.MethodologyWe investigated FOXE1 interactions within in vitro thyroid cell models and human thyroid tissue using a combination of immunoprecipitation (IP), chromatin IP (ChIP) and gene reporter assays.ConclusionsFOXE1 interacts with ELK1 on thyroid relevant gene promoters, establishing a new regulatory pathway for its role in adult thyroid function. Co-regulation of TERT suggests a mechanism by which allelic variants in/near FOXE1 are associated with thyroid cancer risk.
Highlights
Thyroid cancer is the most commonly occurring endocrine malignancy, accounting for 1% of all cancer diagnoses each year
Using a combination of electromobility shift assays, TERT promoter assays and siRNA-silencing, we found that FOXE1 positively regulated TERT expression in a manner dependent upon its association with ELK1
FOXE1 interacts with ELK1 on thyroid relevant gene promoters, establishing a new regulatory pathway for its role in adult thyroid function
Summary
Thyroid cancer is the most commonly occurring endocrine malignancy, accounting for 1% of all cancer diagnoses each year. Recent genetic studies have identified germline allelic variation in and near FOXE1 to be strongly associated www.impactjournals.com/oncotarget with non-medullary thyroid cancer risk including single nucleotide variants rs965513[A] (56 kb upstream of FOXE1) [13,14,15,16,17,18] and rs1867277[A] (within its promoter) [19,20,21], and variation within the FOXE1 polyalanine tract [22,23,24]; resolution of causal variants responsible for the association with thyroid cancer has been difficult due to strong linkage disequilibrium between all three variants. We hypothesised that discovering key FOXE1 transcriptional partners would in turn identify regulatory pathways relevant to its role in oncogenesis
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