title: Suppression of the grainyhead transcription factor 2 gene (GRHL2) inhibits the proliferation, migration, invasion and mediates cell cycle arrest of ovarian cancer cells.
abstract: Previously, we have identified the Grainyhead transcription factor 2 gene (GRHL2) as notably hypomethylated in high-grade (HG) serous epithelial ovarian tumors, compared with normal ovarian tissues. GRHL2 is known for its functions in normal tissue development and wound healing. In the context of cancer, the role of GRHL2 is still ambiguous as both tumorigenic and tumor suppressive functions have been reported for this gene, although a role of GRHL2 in maintaining the epithelial status of cancer cells has been suggested. In this study, we report that GRHL2 is strongly overexpressed in both low malignant potential (LMP) and HG serous epithelial ovarian tumors, which probably correlates with its hypomethylated status. Suppression of the GRHL2 expression led to a sharp decrease in cell proliferation, migration and invasion and induced G1 cell cycle arrest in epithelial ovarian cancer (EOC) cells displaying either epithelial (A2780s) or mesenchymal (SKOV3) phenotypes. However, no phenotypic alterations were observed in these EOC cell lines following GRHL2 silencing. Gene expression profiling and consecutive canonical pathway and network analyses confirmed these data, as in both these EOC cell lines, GRHL2 ablation was associated with the downregulation of various genes and pathways implicated in cell growth and proliferation, cell cycle control and cellular metabolism. Taken together, our data are indicative for a strong oncogenic potential of the GRHL2 gene in EOC progression and support recent findings on the role of GRHL2 as one of the major phenotypic stability factors (PSFs) that stabilize the highly aggressive/metastatic hybrid epithelial/mesenchymal (E/M) phenotype of cancer cells.
authors.affiliation: a Department of Molecular Medicine , Université Laval , Québec , Canada.|b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Adnen
authors.initials: A
authors.lastname: Faddaoui
authors.affiliation: a Department of Molecular Medicine , Université Laval , Québec , Canada.|b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Razan
authors.initials: R
authors.lastname: Sheta
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Bachvarova
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.|c Department of Obstetrics and Gynecology , Université Laval , Québec , Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Plante
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.|c Department of Obstetrics and Gynecology , Université Laval , Québec , Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gregoire
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.|c Department of Obstetrics and Gynecology , Université Laval , Québec , Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Renaud
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.|c Department of Obstetrics and Gynecology , Université Laval , Québec , Canada.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sebastianelli
authors.affiliation: a Department of Molecular Medicine , Université Laval , Québec , Canada.|d Centre de Recherche du CHU de Québec , CHUL , Québec , Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Gobeil
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Chantale
authors.initials: C
authors.lastname: Morin
authors.affiliation: b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Karim
authors.initials: K
authors.lastname: Ghani
authors.affiliation: a Department of Molecular Medicine , Université Laval , Québec , Canada.|b Centre de Recherche du CHU de Québec , L'Hôtel-Dieu de Québec , Québec , Canada.
authors.forename: Dimcho
authors.initials: D
authors.lastname: Bachvarov
mesh_terms: D064113:CRISPR-Cas Systems / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055786:Gene Knockout Techniques; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C470830:GRHL2 protein, human; D034741:RNA, Small Interfering; D014157:Transcription Factors
keywords: CRISPR/Cas9; GRHL2; cancer cell migration/invasion; epithelial ovarian cancer; epithelial-to-mesenchymal transition; microarrays; shRNA