Hippo Pathway mediator TAZ acts as a negative regulator of the sodium iodide symporter

Abstract

Background. TAZ/WWTR1 (transcriptional coactivator with a PDZ-binding domain) is a transcriptional cofactor involved in the Hippo Signalling pathway, which is described to have a key role in the control of cell proliferation, apoptosis, the inhibition of cell-cell contact, stem cell self-renewal and tissue regeneration. TAZ has been reported to regulate these processes through the transactivation of transcription factors in the nucleus, where it has also been shown to interact with Smad2/3-Smad4 complexes favouring nuclear accumulation under TGFβ stimulation. TAZ co-activates Pax8, a master gene of thyroid differentiation, within the thyroglobulin promoter. Furthermore, Pax8 is the main positive regulator of sodium iodide symporter (NIS) expression and it has been reported to interact with Smad3 causing NIS transcriptional repression mediated by TGFβ.Aim. Therefore, the aim of this work was to study the involvement of TAZ in the expression of NIS, since it is an important protein not only for the correct function of the thyroid gland, but also for radioiodide treatment in thyroid cancer.Methods and Results. Strikingly, we observed that TAZ negatively regulates the transcriptional activity of Pax8 within the NIS promoter. Furthermore, we provided evidence that TAZ could play an important role in the downregulation of NIS expression by TGFβ; we detected that TAZ protein is mainly located in the nucleus under treatment with this cytokine and its silencing induces a partial recovery of NIS protein and mRNA levels. Our results also demonstrated an increased expression of TAZ in thyroid carcinoma cell lines, in which NIS levels are typically decreased. Specifically, TAZ nuclear translocation is increased in those thyroid carcinoma cells with mutated BRAFV600E or when this oncogene is conditionally activated. Since we have described that this mutation increases the secretion of TGFβ, this could be connected with the decreased levels of NIS in these cells.Conclusion. This study has shed light on the important role of the Hippo pathway in the regulation of NIS expression in thyroid cells, repressing Pax8 activity and impaired thyroid differentiation. Given that this protein has been identified to be overexpressed in thyroid carcinoma, future research of the role of TAZ in thyroid tumorogenesis will enable development of new strategies to treat thyroid cancer.