EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion

Abstract Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elu...

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Autores principales:	Xiaoqing Yi, Jianfeng Guo, Jing Guo, Si Sun, Ping Yang, Junjie Wang, Yuan Li, Lisha Xie, Jing Cai, Zehua Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/73dc2287caf146d6a51c6c9b7f2edf27
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spelling	oai:doaj.org-article:73dc2287caf146d6a51c6c9b7f2edf272021-12-02T12:31:50ZEZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion10.1038/s41598-017-03362-z2045-2322https://doaj.org/article/73dc2287caf146d6a51c6c9b7f2edf272017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03362-zhttps://doaj.org/toc/2045-2322Abstract Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elusive. Here, we showed that EZH2 is up-regulated in ovarian cancer and is associated with tumor metastasis and poor survival by mRNA sequencing and microarray results from databases. Tissue microarray and immunohistochemistry results revealed that EZH2 was negatively correlated with the expression of tissue inhibitor of metalloproteinases 2 (TIMP2). EZH2 overexpression inhibited TIMP2 expression and promoted proteolytic activities of matrix metalloproteinases 2 and 9 and vice versa. EZH2 promoted ovarian cancer invasion and migration, which could be largely reversed by TIMP2 down-regulation in vitro and in vivo. Both H3K27me3 inhibition and demethylation could reduce methylation of the TIMP2 promoter and finally reactivate TIMP2 transcription. The presence of EZH2 and H3K27me3 at the TIMP2 promoter was confirmed by chromatin immunoprecipitation. H3K27me3 and DNA methyltransferases at the promoter were significantly increased by EZH2 overexpression. These results suggest that EZH2 inhibits TIMP2 expression via H3K27me3 and DNA methylation, which relieve the repression of MMP and facilitate ovarian cancer invasion and migration.Xiaoqing YiJianfeng GuoJing GuoSi SunPing YangJunjie WangYuan LiLisha XieJing CaiZehua WangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xiaoqing Yi Jianfeng Guo Jing Guo Si Sun Ping Yang Junjie Wang Yuan Li Lisha Xie Jing Cai Zehua Wang EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
description	Abstract Enhancer of zeste homolog 2 (EZH2) is often increased in malignant tumors and is involved in metastasis. EZH2 silences gene expression by tri-methylating the lysine 27 residue of histone H3 (H3K27me3). However, the mechanism underlying EZH2 promotion of ovarian cancer metastasis remains elusive. Here, we showed that EZH2 is up-regulated in ovarian cancer and is associated with tumor metastasis and poor survival by mRNA sequencing and microarray results from databases. Tissue microarray and immunohistochemistry results revealed that EZH2 was negatively correlated with the expression of tissue inhibitor of metalloproteinases 2 (TIMP2). EZH2 overexpression inhibited TIMP2 expression and promoted proteolytic activities of matrix metalloproteinases 2 and 9 and vice versa. EZH2 promoted ovarian cancer invasion and migration, which could be largely reversed by TIMP2 down-regulation in vitro and in vivo. Both H3K27me3 inhibition and demethylation could reduce methylation of the TIMP2 promoter and finally reactivate TIMP2 transcription. The presence of EZH2 and H3K27me3 at the TIMP2 promoter was confirmed by chromatin immunoprecipitation. H3K27me3 and DNA methyltransferases at the promoter were significantly increased by EZH2 overexpression. These results suggest that EZH2 inhibits TIMP2 expression via H3K27me3 and DNA methylation, which relieve the repression of MMP and facilitate ovarian cancer invasion and migration.
format	article
author	Xiaoqing Yi Jianfeng Guo Jing Guo Si Sun Ping Yang Junjie Wang Yuan Li Lisha Xie Jing Cai Zehua Wang
author_facet	Xiaoqing Yi Jianfeng Guo Jing Guo Si Sun Ping Yang Junjie Wang Yuan Li Lisha Xie Jing Cai Zehua Wang
author_sort	Xiaoqing Yi
title	EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
title_short	EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
title_full	EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
title_fullStr	EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
title_full_unstemmed	EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion
title_sort	ezh2-mediated epigenetic silencing of timp2 promotes ovarian cancer migration and invasion
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/73dc2287caf146d6a51c6c9b7f2edf27
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EZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasion

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