THE TRANSCRIPTION FACTOR GRAINYHEAD-LIKE 2 IS A GATEKEEPER OF THE EPITHELIAL STATUS OF OVARIAN CANCER

Abstract

EPITHELIAL OVARIAN CANCER (EOC) IS CLINICALLY HETEROGENEOUS, COMPRISING DIFFERENT HISTOLOGICAL AND MOLECULAR SUBTYPES. MULTIPLE STUDIES HAVE IMPLICATED EPITHELIAL-MESENCHYMAL TRANSITION (EMT), A BIOLOGICAL PROCESS BY WHICH POLARIZED EPITHELIAL CELLS CONVERT INTO MESENCHYMAL PHENOTYPE, TO HAVE SIGNIFICANT CONTRIBUTION TO THE MOLECULAR HETEROGENEITY OF EOC. FROM GENE EXPRESSION ANALYSES OF EOC TUMOURS AND EMT-CHARACTERIZED EOC CELL LINES, GRAINYHEAD-LIKE 2 (GRHL2) EMERGES AS A TRANSCRIPTION FACTOR ESSENTIAL FOR THE MAINTENANCE OF EPITHELIAL PHENOTYPE. SHRNA-MEDIATED KNOCKDOWN OF GRHL2 IN EPITHELIAL-LIKE EOC CELLS RESULTED IN PARTIAL OR FULL EMT, ACCOMPANIED BY AN INCREASE IN CELL MOTILITY, MIGRATION AND INVASION. A COMBINED ANALYSIS OF CHROMATIN-IMMUNOPRECIPITATION SEQUENCING (CHIP-SEQ) AND GENE EXPRESSION MICROARRAY IDENTIFIED A VARIETY OF TARGET GENES REGULATED BY GRHL2, INCLUDING PROTEIN-CODING AND NON-CODING GENES. SOME OF THE EMT-RELATED GENES SUCH AS CDH1, ZEB1 AND MIR200B WERE FOU