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.
Highlights
The Polycomb group protein complexes alter methylation of histone tails and play a critical role during development by compacting chromatin and repressing transcription of differentiation-associated genes
By using a transforming growth factor β1 (TGF-β)-inducible epithelial-to-mesenchymal transition (EMT) model in ovarian cancer (OC) cells, we show that enhancer of zeste homolog 2 (EZH2) is required for maintaining the epithelial characteristics of cancer cells and that erasure of the H3K27me3 marks catalyzed by EZH2 permits transition to a mesenchymal state
Epithelial-to-mesenchymal transition is a cellular process involved in the early phases of development and in cancer metastasis
Summary
The Polycomb group protein complexes alter methylation of histone tails and play a critical role during development by compacting chromatin and repressing transcription of differentiation-associated genes. Among the best studied chromatin regulators is enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the polycomb repressor complex 2 (PRC2). Deregulation and function-altering mutations of chromatin modifiers [2,3,4] have been widely reported in cancer, including in ovarian cancer (OC), but their involvement and regulation in tumorigenesis are complex and remain not fully understood [5]. TGF-β exerts both tumor suppressor and oncogenic activities in cancer [8] and while its effects are mediated transcriptionally, the cytokine has recently been shown to alter chromatin organization [9]. We sought to determine whether chromatin modifications imparted by EZH2 play a role in the response of OC cells to TGF-β
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