title: Thyroid transcription factor FOXE1 interacts with ETS factor ELK1 to co-regulate TERT.
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.
  
  
  METHODS
  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.
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Martyn
authors.initials: M
authors.lastname: Bullock
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Grace
authors.initials: G
authors.lastname: Lim
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.|University of Sydney, Sydney, Australia.
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.|University of Sydney, Sydney, Australia.
authors.forename: In Ho
authors.initials: IH
authors.lastname: Choi
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.|University of Sydney, Sydney, Australia.
authors.forename: Shivansh
authors.initials: S
authors.lastname: Kochhar
authors.affiliation: University of Sydney, Sydney, Australia.|Storr Liver Centre, Westmead Millennium Institute for Medical Research, Westmead Hospital, Sydney, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Cancer Genetics Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, Australia.|University of Sydney, Sydney, Australia.|Department of Endocrinology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Clifton-Bligh
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000209:etiology*; D050807:ets-Domain Protein Elk-1 / Q000502:physiology*
chemical_list: D002070:Butadienes; C494112:ELK1 protein, human; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D009570:Nitriles; C113580:U 0126; D050807:ets-Domain Protein Elk-1; D007453:Iodide Peroxidase; D020929:Mitogen-Activated Protein Kinase Kinases; C509186:TERT protein, human; D019098:Telomerase
keywords: BRAF-ERK pathway; ELK1; FOXE1; TERT; thyroid cancer