title: EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells.
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.
authors: Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Chicago, IL, USA.
authors: Horacio
authors: H
authors: Cardenas
authors: Oakland University William Beaumont School of Medicine, Rochester, MI, USA.
authors: Janice
authors: J
authors: Zhao
authors: Indiana University Department of Medicine, Indianapolis, IN, USA.
authors: Edyta
authors: E
authors: Vieth
authors: Medical Sciences, Indiana University, Bloomington, IN, USA.
authors: Kenneth P
authors: KP
authors: Nephew
authors: Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Chicago, IL, USA.|Northwestern University Feinberg School of Medicine, Department of Medicine, Chicago, IL, USA.|Robert Lurie Cancer Center, Northwestern University, Chicago, IL, USA.
authors: Daniela
authors: D
authors: Matei
mesh_terms: D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008745:Methylation / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011728:Pyridones / Q000494:pharmacology; D034622:RNA Interference; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D000074165:Zinc Finger E-box Binding Homeobox 2 / Q000235:genetics / Q000378:metabolism
chemical_list: C577920:GSK-2816126; D006657:Histones; D007211:Indoles; D011728:Pyridones; D016212:Transforming Growth Factor beta; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: EMT; EZH2; GSK126; H3K27me3; ovarian cancer