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

Horacio Cardenas, Janice Zhao, Edyta Vieth, Kenneth Nephew, Daniela Matei

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)84453-84467
Number of pages15
JournalOncotarget
Volume7
Issue number51
DOIs
StatePublished - 2016

Fingerprint

Epithelial-Mesenchymal Transition
Ovarian Neoplasms
Small Interfering RNA
Polycomb Repressive Complex 2
Chromatin Assembly and Disassembly
Chromatin Immunoprecipitation
Enhancer of Zeste Homolog 2 Protein
Histones
Lysine
Catalytic Domain
Transcription Factors
Maintenance
Phenotype
Gene Expression
Genes
Neoplasms

Keywords

  • EMT
  • EZH2
  • GSK126
  • H3K27me3
  • Ovarian cancer

ASJC Scopus subject areas

  • Oncology

Cite this

EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells. / Cardenas, Horacio; Zhao, Janice; Vieth, Edyta; Nephew, Kenneth; Matei, Daniela.

In: Oncotarget, Vol. 7, No. 51, 2016, p. 84453-84467.

Research output: Contribution to journalArticle

Cardenas, Horacio ; Zhao, Janice ; Vieth, Edyta ; Nephew, Kenneth ; Matei, Daniela. / EZH2 inhibition promotes epithelial-to-mesenchymal transition in ovarian cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 51. pp. 84453-84467.
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