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GRHL2-miR-200-ZEB1 Maintains the Epithelial Status of Ovarian Cancer through Transcriptional Regulation and Histone Modification. (Scientific Reports, Feb 2016)

Vin Yee Chung1, Tuan Zea Tan1, Ming Tan1, Meng Kang Wong1, Kuee Theng Kuay1, Zhe Yang1, Jieru Ye1, Julius Muller2, Cheryl M. Koh2, Ernesto Guccione2, Jean Paul Thiery1, 2, 3 & Ruby Yun-Ju Huang1, 4, 5

1Cancer Science Institute of Singapore, National University of Singapore
2Institute of Molecular and Cell Biology, A*STAR
3Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
4Department of Obstetrics and Gynaecology, National University Hospital
5Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore

Abstract:

Epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, has been implicated to contribute to the molecular heterogeneity of epithelial ovarian cancer (EOC). Here we report that a transcription factor—Grainyhead-like 2 (GRHL2) maintains the epithelial phenotype. EOC tumours with lower GRHL2 levels are associated with the Mes/Mesenchymal molecular subtype and a poorer overall survival. shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype results in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, microRNA-200b/a is identified as the direct transcriptional target of GRHL2 and regulates the epithelial status of EOC through ZEB1 and E-cadherin. Our study demonstrates that loss of GRHL2 increases the levels of histone mark H3K27me3 on promoters and GRHL2-binding sites at miR-200b/a and E-cadherin genes. These findings support GRHL2 as a pivotal gatekeeper of EMT in EOC via miR-200-ZEB1.