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MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity

Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusi...

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Autores principales: Si, Wenzhe, Liu, Xujun, Wei, Rui, Zhang, Yuan, Zhao, Yang, Cui, Liyan, Hong, Tianpei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393561/
https://www.ncbi.nlm.nih.gov/pubmed/30814496
http://dx.doi.org/10.1038/s41419-019-1424-5
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author Si, Wenzhe
Liu, Xujun
Wei, Rui
Zhang, Yuan
Zhao, Yang
Cui, Liyan
Hong, Tianpei
author_facet Si, Wenzhe
Liu, Xujun
Wei, Rui
Zhang, Yuan
Zhao, Yang
Cui, Liyan
Hong, Tianpei
author_sort Si, Wenzhe
collection PubMed
description Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusive. The aim of this study was to explore the function and regulation mechanism of MTA2 in PDAC. As shown in GEO, ICGC, and TCGA databases, a higher expression of MTA2 was noticed in the PDAC tissues than in the normal pancreatic tissues. Moreover, a higher expression level of MTA2 was associated with a shorter overall survival time in these public PDAC databases. We further investigated the underlying mechanisms of these observations by using a chromatin immunoprecipitation (ChIP)-based deep sequencing, luciferase reporter, and quantitative ChIP assays. We identified the repressive binding of MTA2 to the promoter of phosphatase and tensin homolog (PTEN). We also found that Snail recruited MTA2 and HDAC1 to suppress PTEN expression. Ectopic expression and knockdown of MTA2 were performed to evaluate the effects of this gene on PDAC cell proliferation, migration, and invasion. Using CCK-8, colony formation and transwell assays, and a xenograft tumor model, we revealed that MTA2 promoted PDAC cell proliferation, migration, and invasion in vitro and PDAC tumor growth in vivo by downregulation of PTEN. In benzyl isothiocyanate (BITC)-treated MIA Paca-2 cells and PANC-1 cells, MTA2 level decreased in a dose- and time-dependent manner with concomitant upregulation of PTEN level and downregulation of phosphorylated PI3K and AKT levels, providing evidence of the involvement of MTA2 and PTEN in the regulation of the PI3K/AKT pathway in BITC-mediated PDAC suppression. Collectively, these findings uncover a novel role for MTA2 in the regulation of PDAC progression and help to elucidate the mechanisms involved in this process.
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spelling pubmed-63935612019-02-28 MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity Si, Wenzhe Liu, Xujun Wei, Rui Zhang, Yuan Zhao, Yang Cui, Liyan Hong, Tianpei Cell Death Dis Article Metastasis-associated protein 2 (MTA2) is a core subunit of the nucleosome remodeling and deacetylating (NuRD) complex and functions by mediating chromatin remodeling and gene silencing. However, its biological actions and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remain elusive. The aim of this study was to explore the function and regulation mechanism of MTA2 in PDAC. As shown in GEO, ICGC, and TCGA databases, a higher expression of MTA2 was noticed in the PDAC tissues than in the normal pancreatic tissues. Moreover, a higher expression level of MTA2 was associated with a shorter overall survival time in these public PDAC databases. We further investigated the underlying mechanisms of these observations by using a chromatin immunoprecipitation (ChIP)-based deep sequencing, luciferase reporter, and quantitative ChIP assays. We identified the repressive binding of MTA2 to the promoter of phosphatase and tensin homolog (PTEN). We also found that Snail recruited MTA2 and HDAC1 to suppress PTEN expression. Ectopic expression and knockdown of MTA2 were performed to evaluate the effects of this gene on PDAC cell proliferation, migration, and invasion. Using CCK-8, colony formation and transwell assays, and a xenograft tumor model, we revealed that MTA2 promoted PDAC cell proliferation, migration, and invasion in vitro and PDAC tumor growth in vivo by downregulation of PTEN. In benzyl isothiocyanate (BITC)-treated MIA Paca-2 cells and PANC-1 cells, MTA2 level decreased in a dose- and time-dependent manner with concomitant upregulation of PTEN level and downregulation of phosphorylated PI3K and AKT levels, providing evidence of the involvement of MTA2 and PTEN in the regulation of the PI3K/AKT pathway in BITC-mediated PDAC suppression. Collectively, these findings uncover a novel role for MTA2 in the regulation of PDAC progression and help to elucidate the mechanisms involved in this process. Nature Publishing Group UK 2019-02-27 /pmc/articles/PMC6393561/ /pubmed/30814496 http://dx.doi.org/10.1038/s41419-019-1424-5 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Si, Wenzhe
Liu, Xujun
Wei, Rui
Zhang, Yuan
Zhao, Yang
Cui, Liyan
Hong, Tianpei
MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title_full MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title_fullStr MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title_full_unstemmed MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title_short MTA2-mediated inhibition of PTEN leads to pancreatic ductal adenocarcinoma carcinogenicity
title_sort mta2-mediated inhibition of pten leads to pancreatic ductal adenocarcinoma carcinogenicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393561/
https://www.ncbi.nlm.nih.gov/pubmed/30814496
http://dx.doi.org/10.1038/s41419-019-1424-5
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