Oncotarget

Research Papers:

Thyroid transcription factor FOXE1 interacts with ETS factor ELK1 to co-regulate TERT

Martyn Bullock, Grace Lim, Cheng Li, In Ho Choi, Shivansh Kochhar, Chris Liddle, Lei Zhang and Roderick J. Clifton-Bligh _

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Oncotarget. 2016; 7:85948-85962. https://doi.org/10.18632/oncotarget.13288

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Abstract

Martyn Bullock1, Grace Lim1, Cheng Li1,2, In Ho Choi1,2, Shivansh Kochhar1,2, Chris Liddle2,3, Lei Zhang4, Roderick J. Clifton-Bligh1,2,5

1Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia

2University of Sydney, Sydney, Australia

3Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead Hospital, Sydney, Australia

4Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK

5Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia

Correspondence to:

Roderick J. Clifton-Bligh, email: [email protected].au

Keywords: thyroid cancer, BRAF-ERK pathway, FOXE1, ELK1, TERT

Received: February 17, 2016     Accepted: November 06, 2016     Published: November 11, 2016

ABSTRACT

Background: Although 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.

Results: In 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.

Methodology: We 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.

Conclusions: FOXE1 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.


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