Abstract A027: Identification and role of mega-trans-factors in epithelial ovarian cancer


 Epithelial ovarian cancer (EOC) accounts for over 90% of ovarian cancer cases and results in 14,000 U.S. deaths annually. It is the leading cause of death attributed to gynecological cancers. Aside from recent scientific advances, the 5-year survival rate for late-stage invasive EOC has been near 30% for several decades. Our computational transcriptional regulatory analysis in low-grade serous ovarian cancers (LGSOCs) vs. high-grade serous ovarian cancers (HGSOCs) identified a master regulatory complex, Megatrans complex (MTC), the objective of this study is to identify role of MTC in ovarian cancer, never reported before. MTC is estrogen-responsive master regulatory complex containing a multitude of DNA-binding transcription factors (MTC_TFs), including ER-alpha, RAR-alpha, GATA3, AP2-gamma, STAT1, AP1, RUNX1, and FOXA1. Given that we found MTC gene targets are downregulated in HGSOC, and that some target genes are prognostic for poor patient survival, understanding the function of MTC and modulating its activity may improve prognostic outcomes for HGSOC patients. We hypothesize that different combinations of MTC_TFs produce distinct regulatory signatures in different grades of ovarian cancers. In the grade, PEO4, cell line, we have confirmed MTC formation using a gel filtration assay and identified the presence of MTC_TFs by western blot. We discovered tumor suppressor, PITX1, as a novel MTC_TF in ovarian cancer, not previously reported in a breast cancer MTC. Methylation analysis revealed PITX1 and ER-alpha binding to hypomethylated, but repressed promoters and ChIP-seq analysis revealed PITX1 co-occupying 98.8% of ER-alpha binding sites, suggesting a repressive role of PITX1 on ER-alpha regulated genes. We are performing additional ChIP-seq experiments of MTC_TFs in HGSOC and LGSOC cell lines to test whether the MTC_TF binding distinguishes their regulatory signatures. Our findings of a nuclear hormone-regulated MTC complex controlling the transcriptional landscape of ovarian cancer are expected to facilitate new breakthroughs in disease treatment.
 Citation Format: Sushil Kumar Jaiswal, Kevin Fedkenheuer, Laura Elnitski. Identification and role of mega-trans-factors in epithelial ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A027.