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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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-06-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-03362-z |
| _version_ | 1819042297663193088 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-21T09:38:39Z |
| format | Article |
| id | doaj.art-73dc2287caf146d6a51c6c9b7f2edf27 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-21T09:38:39Z |
| publishDate | 2017-06-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj.art-73dc2287caf146d6a51c6c9b7f2edf272022-12-21T19:08:32ZengNature PortfolioScientific Reports2045-23222017-06-017111610.1038/s41598-017-03362-zEZH2-mediated epigenetic silencing of TIMP2 promotes ovarian cancer migration and invasionXiaoqing Yi0Jianfeng Guo1Jing Guo2Si Sun3Ping Yang4Junjie Wang5Yuan Li6Lisha Xie7Jing Cai8Zehua Wang9Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, First Affiliated Hospital, School of Medicine, Shihezi UniversityDepartment of Obstetrics and Gynecology, Renhe Hospital, Three Gorges UniversityDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract 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.https://doi.org/10.1038/s41598-017-03362-z |
| spellingShingle | 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 Scientific Reports |
| title | 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_short | 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 |
| url | https://doi.org/10.1038/s41598-017-03362-z |
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