Grainyhead-like 2 (GRHL2) maintains the epithelial status of ovarian cancer through miR-200-ZEB1 regulatory networks (expression)

Epithelial ovarian cancer (EOC) is clinically heterogeneous, comprising different histological and biological subtypes. Multiple studies have implicated epithelial-mesenchymal transition (EMT), a biological process by which polarized epithelial cells convert into a mesenchymal phenotype, to contribute significantly to this molecular heterogeneity of EOC. From gene expression analyses of a collection of EMT-characterized EOC cell lines, we found that the expression of the transcription factor Grainyhead-like 2 (GRHL2) correlates with E-cadherin expression and the epithelial phenotype. EOC tumors with lower levels of GRHL2 are associated with the Mes (mesenchymal) molecular subtype and show poorer overall survival in patients. Here, we demonstrate that shRNA-mediated knockdown of GRHL2 in EOC cells with an epithelial phenotype resulted in EMT changes, with increased cell migration, invasion and motility. By ChIP-sequencing and gene expression microarray, we identified a variety of target genes regulated by GRHL2, including protein-coding and non-coding genes. Our data suggest that GRHL2 maintains the epithelial phenotype of EOC cells through the regulatory networks of miR-200b/a, ZEB1 and E-cadherin. These findings support GRHL2 as a crucial player in the molecular heterogeneity of EOC.

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Chung VY, Tan TZ, Tan M, Wong MK, Kuay KT, Yang Z, Ye J, Muller J, Koh CM, Guccione E, Thiery JP, Huang RY