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Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer
Background: 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 c...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142903/ https://www.ncbi.nlm.nih.gov/pubmed/30271381 http://dx.doi.org/10.3389/fendo.2018.00527 |
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author | Roehlen, Natascha Doering, Claudia Hansmann, Martin-Leo Gruenwald, Frank Vorlaender, Christian Bechstein, Wolf Otto Holzer, Katharina Badenhoop, Klaus Penna-Martinez, Marissa |
author_facet | Roehlen, Natascha Doering, Claudia Hansmann, Martin-Leo Gruenwald, Frank Vorlaender, Christian Bechstein, Wolf Otto Holzer, Katharina Badenhoop, Klaus Penna-Martinez, Marissa |
author_sort | Roehlen, Natascha |
collection | PubMed |
description | Background: 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 FOXO3a 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. Methods: The SNP's FOXO3a 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)(2)D(3) and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro. Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (p(corrected) = p(c) = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (p(c) = 0.02 and p(c) = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)(2)D(3) showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05). Conclusions: FOXO3a 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. |
format | Online Article Text |
id | pubmed-6142903 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61429032018-09-28 Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer Roehlen, Natascha Doering, Claudia Hansmann, Martin-Leo Gruenwald, Frank Vorlaender, Christian Bechstein, Wolf Otto Holzer, Katharina Badenhoop, Klaus Penna-Martinez, Marissa Front Endocrinol (Lausanne) Endocrinology Background: 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 FOXO3a 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. Methods: The SNP's FOXO3a 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)(2)D(3) and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro. Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (p(corrected) = p(c) = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (p(c) = 0.02 and p(c) = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)(2)D(3) showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05). Conclusions: FOXO3a 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. Frontiers Media S.A. 2018-09-11 /pmc/articles/PMC6142903/ /pubmed/30271381 http://dx.doi.org/10.3389/fendo.2018.00527 Text en Copyright © 2018 Roehlen, Doering, Hansmann, Gruenwald, Vorlaender, Bechstein, Holzer, Badenhoop and Penna-Martinez. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Roehlen, Natascha Doering, Claudia Hansmann, Martin-Leo Gruenwald, Frank Vorlaender, Christian Bechstein, Wolf Otto Holzer, Katharina Badenhoop, Klaus Penna-Martinez, Marissa Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title_full | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title_fullStr | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title_full_unstemmed | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title_short | Vitamin D, FOXO3a, and Sirtuin1 in Hashimoto's Thyroiditis and Differentiated Thyroid Cancer |
title_sort | vitamin d, foxo3a, and sirtuin1 in hashimoto's thyroiditis and differentiated thyroid cancer |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142903/ https://www.ncbi.nlm.nih.gov/pubmed/30271381 http://dx.doi.org/10.3389/fendo.2018.00527 |
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