Research Papers:

EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells

Horacio Cardenas, Janice Zhao, Edyta Vieth, Kenneth P. Nephew and Daniela Matei _

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Oncotarget. 2016; 7:84453-84467. https://doi.org/10.18632/oncotarget.11497

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Horacio Cardenas1, Janice Zhao2, Edyta Vieth3, Kenneth P. Nephew4, Daniela Matei1,5,6

1Northwestern University Feinberg School of Medicine, Department of Obstetrics and Gynecology, Chicago, IL, USA

2Oakland University William Beaumont School of Medicine, Rochester, MI, USA

3Indiana University Department of Medicine, Indianapolis, IN, USA

4Medical Sciences, Indiana University, Bloomington, IN, USA

5Northwestern University Feinberg School of Medicine, Department of Medicine, Chicago, IL, USA

6Robert Lurie Cancer Center, Northwestern University, Chicago, IL, USA

Correspondence to:

Daniela Matei, email: [email protected]

Horacio Cardenas, email: [email protected]

Keywords: ovarian cancer, EZH2, EMT, H3K27me3, GSK126

Received: March 24, 2016    Accepted: August 09, 2016    Published: August 22, 2016


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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