Abstract 2733: Super-enhancers in oncogene upregulation in high-grade ovarian serous carcinoma proliferation and platinum-resistance
Authors: Zhongmou Jin, Kristin Adams, Kendra Wendt, Josie Wood, Sydney Olson, Jessica D. Lang
Journal: Cancer Research (2025)

Abstract The most common subtype of ovarian cancer, High-Grade Serous Ovarian Carcinoma (HGSC), bears an exceptionally high level of chromosomal instability including chromosomal recombination and copy number variation. Many oncogenes are amplified in HGSC, of which some of the most frequently examined ones include MYC, PAX8 and CCNE1. Although downstream pathways of those genes have been repeatedly studied, epigenetic features of many of them are relatively unknown, as they could involve mechanisms that additively and continuously promote oncogene expression that may contribute to the aggressiveness of HGSCs. In our study, we specifically focus on super-enhancers (SEs), large transcriptional hubs known to drive oncogene expression. We aim to assess whether SEs are hijacked coordinately with copy number alteration in HGSCs. We were able to apply a multi-omic approach that includes bulk RNA sequencing, histone post-translational modification CUT&amp;Tag, and Hi-C analysis to not only identify SE regions in HGSC cell lines but link them to the genes they regulate. With integration of these layers of data, we show that there is a positive correlation between HGSC SEs and gene expression changes in HGSCs, in the context of both cancer growth as well as drug resistance acquisition. We observed that SEs are almost always statistically associated with higher gene expression of their target genes compared to enhancers. We also explored changes in SEs in the context of platinum resistance acquisition in our HGSC cell lines, with the observation that gain of new SEs are associated with increase in gene expression and vice versa. Together, these findings support the possibility that SEs could be critical for essential oncogene expression and changes that lead to drug resistance. We then explored if the copy number amplification (CNA) known associated with cancer genome also plays a role in SE regulation of oncogene expression. We found in almost all HGSC cell lines tested that compared to non-oncogene-related SEs, oncogene-related SEs are significantly more likely to be in copy number amplified regions of the genome (p &amp;lt; 0.001), rendering it a potential mechanism contributing to SE associated oncogene upregulation. Based on this result, we are launching screens for specific SE-oncogene interaction in locating functionally important epigenetic marks with CRISPRi, as well as to leverage our existing Hi-C contact data in combination with long-read sequencing to understand the chromatin architecture in the context of CNV.In summary, in this study we observed promising trends supporting SE hijacking in oncogene upregulation and CNA as a potential factor that contributes to SE regulation. We hope that understanding the mechanisms and context behind epigenetic regulation may lead to rational use of epigenetic inhibitors for cancers driven by copy number alterations to otherwise untargetable oncogenes. Citation Format: Zhongmou Jin, Kristin Adams, Kendra Wendt, Josie Wood, Sydney Olson, Jessica D. Lang. Super-enhancers in oncogene upregulation in high-grade ovarian serous carcinoma proliferation and platinum-resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2733.