title: GRHL2-miR-200-ZEB1 maintains the epithelial status of ovarian cancer through transcriptional regulation and histone modification.
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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Vin Yee
authors.initials: VY
authors.lastname: Chung
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Tuan Zea
authors.initials: TZ
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Meng Kang
authors.initials: MK
authors.lastname: Wong
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Kuee Theng
authors.initials: KT
authors.lastname: Kuay
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.
authors.forename: Jieru
authors.initials: J
authors.lastname: Ye
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 13867.
authors.forename: Julius
authors.initials: J
authors.lastname: Muller
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 13867.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Koh
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 13867.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.|Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Proteos, Singapore 13867.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore, 117596.
authors.forename: Jean Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599.|Department of Obstetrics and Gynaecology, National University Hospital, 5 Lower Kent Ridge Road, Singapore 119074.|Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, MD6, #14-02T, Singapore 117599.
authors.forename: Ruby Yun-Ju
authors.initials: RY
authors.lastname: Huang
mesh_terms: D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D006657:Histones; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1