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.

Novel Androgen Receptor Coregulator GRHL2 Exerts Both Oncogenic and Antimetastatic Functions in Prostate Cancer

“…Recent studies have elucidated transcriptional targets via which GRHL2 suppresses EMT in breast and ovarian cancer (38,40). For example, GRHL2 binds to promoter and/or enhancer elements to directly activate CDH1 (E-cadherin), TJP1 (ZO-1), CLDN4, ELF3, EPCAM and RAB25 , thereby promoting an epithelial phenotype.…”

“…Recent work suggests that dual functionality of GRHL2 (i.e. growth-promoting but EMT/invasion-suppressing) could be a generalizable phenomenon in carcinomas (40,45). …”

Grainyhead-like 2 in development and cancer

“…GRHL2 directly activates the transcription of microRNA-200b/a which regulates the epithelial status of epithelial ovarian cancer through inhibition of the expression of ZEB1 and E-cadherin. 47 ZEB1 can inhibit expression of GRHL2 as well; 45 GRHL2 and ZEB1 form a negative feedback loop.…”

A new dimension in drug discovery: reversing epithelial–mesenchymal transition (EMT)

“…Grainyhead-like 2 (GRHL2) has been demonstrated as an EMT suppressor that forms a negative regulatory loop with ZEB1 and miR200 family. 10 GRHL2 binds to the enhancer site at the second intron of the E-cadherin gene; furthermore, GRHL2 regulates its promoter activity via local DNA looping. 11 Since GRHL2 is an important epithelial gatekeeper, GRHL2 target genes could be candidates for the EpI screen.…”

“…3 As the direct transcriptional target for GRHL2, ERBB3 expression would be downregulated during EMT, and GRHL2 is lost. 10 Thus, ERBB3 -EpI activity could be utilized as a secondary validation, 3 and it could be applied at the initial phase of EpI screen.…”