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The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3
NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364405/ https://www.ncbi.nlm.nih.gov/pubmed/28338101 http://dx.doi.org/10.1038/srep45266 |
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author | Ni, Lulu Wang, Lixin Yao, Chao Ni, Zhongya Liu, Fei Gong, Chenyuan Zhu, Xiaowen Yan, Xuewei Watowich, Stephanie S. Lee, Dean A. Zhu, Shiguo |
author_facet | Ni, Lulu Wang, Lixin Yao, Chao Ni, Zhongya Liu, Fei Gong, Chenyuan Zhu, Xiaowen Yan, Xuewei Watowich, Stephanie S. Lee, Dean A. Zhu, Shiguo |
author_sort | Ni, Lulu |
collection | PubMed |
description | NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation. In this study, we investigated regulation of NKG2D expression in NK cells by VPA and entinostat by assessing protein expression, phosphorylation, and interaction of HDACs and STAT3. We find that VPA selectively inhibits STAT3 tyrosine705 phosphorylation, but entinostat does not. STAT3 complexes with HDAC3, and HDAC3 inhibition represses STAT3 phosphorylation and therefore NKG2D expression. NK cells from STAT3 wild-type mice downregulate NKG2D in response to VPA, but not NK cells from STAT3 knockout mice. These results show that VPA is a potent inhibitor of STAT3 phosphorylation and demonstrate that histone acetylation and STAT3 tyrosine705 phosphorylation cooperate in regulating NKG2D expression in NK cells. |
format | Online Article Text |
id | pubmed-5364405 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-53644052017-03-24 The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 Ni, Lulu Wang, Lixin Yao, Chao Ni, Zhongya Liu, Fei Gong, Chenyuan Zhu, Xiaowen Yan, Xuewei Watowich, Stephanie S. Lee, Dean A. Zhu, Shiguo Sci Rep Article NKG2D is a major activating receptor of NK cells and plays a critical role in tumor immunosurveillance. NKG2D expression in NK cells is inhibited by the histone deacetylase (HDAC) inhibitor valproic acid (VPA) and enhanced by the narrow-spectrum HDAC inhibitor entinostat. We previously demonstrated that entinostat enhanced NKG2D transcription by increasing acetylation of Histones H3 and H4. However, the mechanism by which VPA reduces NKG2D expression in NK cells is not known. We have also shown that NKG2D transcription is regulated by STAT3 phosphorylation. In this study, we investigated regulation of NKG2D expression in NK cells by VPA and entinostat by assessing protein expression, phosphorylation, and interaction of HDACs and STAT3. We find that VPA selectively inhibits STAT3 tyrosine705 phosphorylation, but entinostat does not. STAT3 complexes with HDAC3, and HDAC3 inhibition represses STAT3 phosphorylation and therefore NKG2D expression. NK cells from STAT3 wild-type mice downregulate NKG2D in response to VPA, but not NK cells from STAT3 knockout mice. These results show that VPA is a potent inhibitor of STAT3 phosphorylation and demonstrate that histone acetylation and STAT3 tyrosine705 phosphorylation cooperate in regulating NKG2D expression in NK cells. Nature Publishing Group 2017-03-24 /pmc/articles/PMC5364405/ /pubmed/28338101 http://dx.doi.org/10.1038/srep45266 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Ni, Lulu Wang, Lixin Yao, Chao Ni, Zhongya Liu, Fei Gong, Chenyuan Zhu, Xiaowen Yan, Xuewei Watowich, Stephanie S. Lee, Dean A. Zhu, Shiguo The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title | The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title_full | The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title_fullStr | The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title_full_unstemmed | The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title_short | The histone deacetylase inhibitor valproic acid inhibits NKG2D expression in natural killer cells through suppression of STAT3 and HDAC3 |
title_sort | histone deacetylase inhibitor valproic acid inhibits nkg2d expression in natural killer cells through suppression of stat3 and hdac3 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364405/ https://www.ncbi.nlm.nih.gov/pubmed/28338101 http://dx.doi.org/10.1038/srep45266 |
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