Article ; Online: EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells.
2016 Volume 7, Issue 51, Page(s) 84453–84467
Abstract: ... roles of EZH2-catalyzed H3K27me3 during EMT in ovarian cancer (OC) cells. TGF-β-induced EMT in SKOV3 OC ... of epithelial-to-mesenchymal transition (EMT), which is regulated by gene expression and chromatin remodeling changes. The enhancer ... cells was associated with decreased levels of EZH2 and H3K27me3 (P<0.05). These effects were delayed ...
| Abstract | Cancer cells acquire essential characteristics for metastatic dissemination through the process of epithelial-to-mesenchymal transition (EMT), which is regulated by gene expression and chromatin remodeling changes. The enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) to repress gene transcription. Here we report the functional roles of EZH2-catalyzed H3K27me3 during EMT in ovarian cancer (OC) cells. TGF-β-induced EMT in SKOV3 OC cells was associated with decreased levels of EZH2 and H3K27me3 (P<0.05). These effects were delayed (~72 h relative to EMT initiation) and coincided with increased (>15-fold) expression of EMT-associated transcription factors ZEB2 and SNAI2. EZH2 knockdown (using siRNA) or enzymatic inhibition (by GSK126) induced EMT-like changes in OC cells. The EMT regulator ZEB2 was upregulated in cells treated with either approach. Furthermore, TGF-β enhanced expression of ZEB2 in EZH2 siRNA- or GSK126-treated cells (P<0.01), suggesting that H3K27me3 plays a role in TGF-β-stimulated ZEB2 induction. Chromatin immunoprecipitation assays confirmed that TGF-β treatment decreased binding of EZH2 and H3K27me3 to the ZEB2 promoter (P<0.05). In all, these results demonstrate that EZH2, by repressing ZEB2, is required for the maintenance of an epithelial phenotype in OC cells. |
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| MeSH term(s) | Cell Line, Tumor ; Enhancer of Zeste Homolog 2 Protein/antagonists & inhibitors ; Enhancer of Zeste Homolog 2 Protein/genetics ; Enhancer of Zeste Homolog 2 Protein/metabolism ; Epithelial-Mesenchymal Transition/drug effects ; Epithelial-Mesenchymal Transition/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Histones/metabolism ; Humans ; Indoles/pharmacology ; Methylation/drug effects ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Promoter Regions, Genetic/genetics ; Protein Binding ; Pyridones/pharmacology ; RNA Interference ; Transforming Growth Factor beta/pharmacology ; Zinc Finger E-box Binding Homeobox 2/genetics ; Zinc Finger E-box Binding Homeobox 2/metabolism |
| Chemical Substances | GSK-2816126 ; Histones ; Indoles ; Pyridones ; Transforming Growth Factor beta ; ZEB2 protein, human ; Zinc Finger E-box Binding Homeobox 2 ; EZH2 protein, human (EC 2.1.1.43) ; Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43) |
| Language | English |
| Publishing date | 2016-09-14 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 2560162-3 |
| ISSN | 1949-2553 ; 1949-2553 |
| ISSN (online) | 1949-2553 |
| ISSN | 1949-2553 |
| DOI | 10.18632/oncotarget.11497 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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