AUTHOR=Roehlen Natascha , Doering Claudia , Hansmann Martin-Leo , Gruenwald Frank , Vorlaender Christian , Bechstein Wolf Otto , Holzer Katharina , Badenhoop Klaus , Penna-Martinez Marissa 

TITLE=Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer

JOURNAL=Frontiers in Endocrinology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00527

DOI=10.3389/fendo.2018.00527

ISSN=1664-2392

ABSTRACT=<p><bold>Background:</bold> Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in <italic>FOXO3a</italic> gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects.</p><p><bold>Methods:</bold> The SNP's <italic>FOXO3a</italic> rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)<sub>2</sub>D<sub>3</sub> and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and <italic>FOXO3a</italic> gene expression <italic>in vitro</italic>.</p><p><bold>Results:</bold> Patients with DTC tended to carry more often allele C in <italic>FOXO3a</italic> rs4946936 in comparison to HC (p<sub>corrected</sub> = p<sub>c</sub> = 0.08). <italic>FOXO3a</italic> rs9400239T and rs4945816C was more frequent in HT in comparison to HC (p<sub>c</sub> = 0.02 and p<sub>c</sub> = 0.01, respectively). In both DTC and HT, we could not find a correlation of <italic>FOXO3a</italic> SNP's with vitamin D status. However, on <italic>in vitro</italic> level, 1,25(OH)<sub>2</sub>D<sub>3</sub> showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: <italic>p</italic> = 0.0059, BCPAP: <italic>p</italic> = 0.04) and accompanied by elevated <italic>FOXO3a</italic> gene expression in T-helper cells (<italic>p</italic> = 0.05).</p><p><bold>Conclusions:</bold><italic>FOXO3a</italic> rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.</p>