OR16-4 Genomic Interrogation of the Phytoestrogen Genistein in Ovarian Cancer Cells

Abstract

Abstract Although studies have shown beneficial effects of the phytoestrogen genistein on reducing ovarian cancer risk, little is known at the molecular level regarding how genistein inhibits ovarian cancer growth, with estrogen receptor beta (ERb), a hormone-regulated transcription factor, receiving the bulk of the attention. When endogenous and exogenous ligands engage ERb, the receptor binds to regulatory regions in the genome known as enhancers, where it associates with coregulatory proteins, increases histone modifications associated with active enhancers, promotes chromatin looping, stimulates enhancer transcription and the production of enhancer RNAs, and ultimately regulates target gene transcription. Since signaling pathways converge at the transcriptome level, an unbiased approach is needed to examine how genistein acts to suppress ovarian cancer growth beyond ERb. We have previously used global run-on sequencing (GRO-seq), a high-throughput method that identifies the location and orientation of all transcriptionally active RNA polymerases across the genome, to identify active enhancers based on enhancer transcription and enrichment of the aforementioned genomic features. To determine the genomic responses upon genistein treatment in ovarian cancer cells, we have used PRO-seq to characterize the enhancer landscape in OVCAR3 and OVCAR4 ovarian cancer cell lines treated with genistein. The advantage of this method is the lack of a priori assumptions needed to determine which signaling pathways are regulated by genistein, since PRO-seq allows pathway determination based on the universe of active enhancers. Ultimately, this approach will allow us to uncover signaling pathways beyond ERb and determine how genistein acts as a signaling ligand to change the transcriptome in ovarian cancer cells. Presentation: Sunday, June 12, 2022 11:45 a.m. - 12:00 p.m.