GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification

• DOI: 10.1038/srep19943
• Publication Date: 2016-02-18T11:06:40Z
• Authors: Vin Yee Chung; Tuan Zea Tan; Ming Tan; Meng Kang Wong; Kuee Theng Kuay; Zhe Yang; Jieru Ye; Julius Muller; Cheryl M. Koh; Ernesto Guccione; Jean Paul Thiery; Ruby Yun-Ju Huang
• Keywords: 0301 basic medicine; Epithelial-Mesenchymal Transition; Transcription, Genetic; epithelial mesenchymal transition; 610; histone; Response Elements; MIRN200 microRNA; Article; Cell Line; 618; Histones; 03 medical and health sciences; tumor protein; Genetic; Cell Line, Tumor; Humans; genetics; human; RNA, Neoplasm; transcription factor; Ovarian Neoplasms; Tumor; microRNA; genetic transcription; tumor cell line; Post-Translational; protein processing; Zinc Finger E-box-Binding Homeobox 1; GRHL2 protein; ZEB1 protein; DNA responsive element; DNA binding protein; Neoplasm Proteins; 3. Good health; DNA-Binding Proteins; MicroRNAs; female; ovary tumor; RNA; Neoplasm; pathology; Female; transcription factor ZEB1; metabolism; Transcription; Protein Processing, Post-Translational; Transcription Factors

AbstractEpithelial-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.