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

• Published in: Scientific reports Vol. 6; no. 1; p. 19943
• Main Authors: Chung, Vin Yee, Tan, Tuan Zea, Tan, Ming, Wong, Meng Kang, Kuay, Kuee Theng, Yang, Zhe, Ye, Jieru, Muller, Julius, Koh, Cheryl M., Guccione, Ernesto, Thiery, Jean Paul, Huang, Ruby Yun-Ju
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.02.2016; Nature Publishing Group
• Subjects: 13/106; 13/109; 14; 14/19; 45/15; 631/67; 631/80/79; 631/80/84; Cell adhesion & migration; Cell Line, Tumor; Cell migration; DNA microarrays; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; E-cadherin; Epithelial cells; Epithelial-Mesenchymal Transition; Female; Gene expression; Gene regulation; Genotype & phenotype; Heterogeneity; Histones - genetics; Histones - metabolism; Humanities and Social Sciences; Humans; Mesenchyme; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Promoters; Protein Processing, Post-Translational; Response Elements; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; Science; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Tumors; Zinc Finger E-box-Binding Homeobox 1 - genetics; Zinc Finger E-box-Binding Homeobox 1 - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep19943

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.