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Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression
Sex-determining region Y box 6 (SOX6) has been described as a tumor-suppressor gene in several cancers. Our previous work has suggested that SOX6 upregulated p21(Waf1/Cip1)(p21) expression in a p53-dependent manner; however, the underlying mechanism has remained elusive. In this study, we confirmed...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820682/ https://www.ncbi.nlm.nih.gov/pubmed/26119940 http://dx.doi.org/10.1038/onc.2015.234 |
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author | Wang, J Ding, S Duan, Z Xie, Q Zhang, T Zhang, X Wang, Y Chen, X Zhuang, H Lu, F |
author_facet | Wang, J Ding, S Duan, Z Xie, Q Zhang, T Zhang, X Wang, Y Chen, X Zhuang, H Lu, F |
author_sort | Wang, J |
collection | PubMed |
description | Sex-determining region Y box 6 (SOX6) has been described as a tumor-suppressor gene in several cancers. Our previous work has suggested that SOX6 upregulated p21(Waf1/Cip1)(p21) expression in a p53-dependent manner; however, the underlying mechanism has remained elusive. In this study, we confirmed that SOX6 can suppress cell proliferation in vitro and in vivo by stabilizing p53 protein and subsequently upregulating p21. Co-immunoprecipitation and immunocytofluorescence assays demonstrated that SOX6 can promote formation of the p14ARF-HDM2-p53 ternary complex by promoting translocation of p14ARF (p14 alternate reading frame tumor suppressor) to the nucleoplasm, thereby inhibiting HDM2-mediated p53 nuclear export and degradation. Chromatin immunoprecipitation combined with PCR assay proved that SOX6 can bind to a potential binding site in the regulatory region of the c-Myc gene. Furthermore, we confirmed that SOX6 can downregulate the expression of c-Myc, as well as its direct target gene nucleophosmin 1 (NPM1), and that the SOX6-induced downregulation of NPM1 is linked to translocation of p14ARF to the nucleoplasm. Finally, we showed that the highly conserved high-mobility group (HMG) domain of SOX6 is required for SOX6-mediated p53 stabilization and tumor inhibitory activity. Collectively, these results reveal a new mechanism of SOX6-mediated tumor suppression involving p21 upregulation via the p14ARF-HDM2-p53 axis in an HMG domain-dependent manner. |
format | Online Article Text |
id | pubmed-4820682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48206822016-04-17 Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression Wang, J Ding, S Duan, Z Xie, Q Zhang, T Zhang, X Wang, Y Chen, X Zhuang, H Lu, F Oncogene Original Article Sex-determining region Y box 6 (SOX6) has been described as a tumor-suppressor gene in several cancers. Our previous work has suggested that SOX6 upregulated p21(Waf1/Cip1)(p21) expression in a p53-dependent manner; however, the underlying mechanism has remained elusive. In this study, we confirmed that SOX6 can suppress cell proliferation in vitro and in vivo by stabilizing p53 protein and subsequently upregulating p21. Co-immunoprecipitation and immunocytofluorescence assays demonstrated that SOX6 can promote formation of the p14ARF-HDM2-p53 ternary complex by promoting translocation of p14ARF (p14 alternate reading frame tumor suppressor) to the nucleoplasm, thereby inhibiting HDM2-mediated p53 nuclear export and degradation. Chromatin immunoprecipitation combined with PCR assay proved that SOX6 can bind to a potential binding site in the regulatory region of the c-Myc gene. Furthermore, we confirmed that SOX6 can downregulate the expression of c-Myc, as well as its direct target gene nucleophosmin 1 (NPM1), and that the SOX6-induced downregulation of NPM1 is linked to translocation of p14ARF to the nucleoplasm. Finally, we showed that the highly conserved high-mobility group (HMG) domain of SOX6 is required for SOX6-mediated p53 stabilization and tumor inhibitory activity. Collectively, these results reveal a new mechanism of SOX6-mediated tumor suppression involving p21 upregulation via the p14ARF-HDM2-p53 axis in an HMG domain-dependent manner. Nature Publishing Group 2016-03-31 2015-06-29 /pmc/articles/PMC4820682/ /pubmed/26119940 http://dx.doi.org/10.1038/onc.2015.234 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 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-nc-nd/4.0/ |
spellingShingle | Original Article Wang, J Ding, S Duan, Z Xie, Q Zhang, T Zhang, X Wang, Y Chen, X Zhuang, H Lu, F Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title | Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title_full | Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title_fullStr | Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title_full_unstemmed | Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title_short | Role of p14ARF-HDM2-p53 axis in SOX6-mediated tumor suppression |
title_sort | role of p14arf-hdm2-p53 axis in sox6-mediated tumor suppression |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820682/ https://www.ncbi.nlm.nih.gov/pubmed/26119940 http://dx.doi.org/10.1038/onc.2015.234 |
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