Abstract B44: Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer

Abstract

Abstract High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer, accounting for over 70% of all cases. HGSOC is frequently complicated by the inevitable development of therapeutic resistance, and thus remains an incurable disease. Recent insights supporting the fallopian tube epithelium (FTE) as a point of origin for HGSOC and the serous tubal intraepithelial carcinoma (STIC) as the precursor lesion for a majority of HGSOCs provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Understanding these key molecular processes is essential to inform the development of next-generation therapies. In this study we investigated the role of the ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis. H2Bub1, catalyzed largely by RNF20, is an epigenetic mark with tumor-suppressor properties. The loss of RNF20/H2Bub1 has been linked with cancer progression. We used immunohistochemistry to characterize the expression of H2Bub1 in HGSOC and FTE precursors. We found that H2Bub1 is lost or downregulated in a large proportion of STICs and HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in serous tumorigenesis. Consistent with our findings, analysis of TCGA data shows that the majority of HGSOCs exhibit heterozygous loss of RNF20. Functionally, we demonstrated that shRNA-mediated knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to increase cell migration and clonogenic growth of immortalized FTE cells. To understand the mechanisms underlying these effects, we performed RNA-seq and proteomics profiling (RPPA) in RNF20 knockdown cells. Major changes were observed in a number of structural, metabolic (e.g., glutamine pathway), and cytokines and inflammatory signaling pathways, providing early mechanistic insights for the observed oncogenic phenotypes. In summary, our study identifies that loss of H2Bub1 is an early epigenetic event in HGSOC that rewires glutamine metabolism and certain inflammatory pathways, which may represent unique therapeutic opportunities. Citation Format: Jagmohan Hooda, Marian Novak, Emily MacDuffie, Melissa Song, Jenny Lester, Vinita Parkash, Gordon B. Mills, Beth Y. Karlan, Moshe Oren, Ronny Drapkin. Early loss of monoubiquitylation of H2B alters key metabolic and immune signaling pathways promoting the progression of high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B44.