Remodeling and Spacing Factor 1, a Reader of Histone H2A Ubiquitination, in High-Grade Serous Ovarian Carcinoma
Abstract
Rationale: Ovarian cancer is the most lethal gynecologic neoplasm and the second most commonly diagnosed gynecological malignancy. High-grade serous ovarian carcinomas (HGSOC) is the most aggressive ovarian cancer subtype and accounts for the most ovarian cancer deaths. However, the molecular mechanism controlling HGSOC aggressiveness remains unclear. Current standard treatment for ovarian cancer is platinum-based chemotherapy. While the initial clinical response rate is good, the 5-year survival rate, particularly for advanced stage ovarian tumors (stage III-IV), remains a dismal 10%. This is primarily due to the development of resistance to platinum-based therapy in both primary and recurrent tumors. The Remodeling and Spacing Factor 1 (RSF1) gene is located in chromosome 11q13.5, a region that is frequently amplified in HGSOC, but not in low-grade or benign ovarian tumors. Clinically, amplification of RSF1 correlates with a significantly shorter survival of ovarian cancer patients. The causal role of RSF1 overexpression in HGSOC aggressiveness has been demonstrated using cell lines and mouse models. Recent studies also reveal that high levels of RSF1 contribute to the chemoresistance and high mortality rate of HGSOC. Therefore, increased RSF1 levels are responsible for, to a large extent, the aggressiveness and chemoresistance of HGSOC. In recent studies, we have identified RSF1 as the reader for histone H2A ubiquitination (H2Aub), a prevalent epigenetic modification that suppresses the expression of key developmental genes. We have delineated the H2Aub binding region in RSF1 to a previously uncharacterized region, which we designated as the ubiquitinated H2A binding (UAB) domain. Our studies further reveal that RSF1 is required for the gene silencing function of H2Aub as well as for the cellular and developmental processes regulated by H2Aub. Therefore, this study reveals the molecular mechanism by which RSF1 regulates gene expression and physiological processes. Objectives: The objectives of this application are (1) to determine whether recognition of H2Aub mark by the UAB domain contributes to the aggressiveness and chemoresistance of HGSOC conferred by overexpressed RSF1 and (2) to test whether RSF1-H2Aub interaction can be targeted for HGSOC treatment. Critical Problem to Be Addressed: Aggressiveness and chemoresistance underlie the high motility rate of HGSOC, but the molecular mechanism controlling these events remains largely unknown. RSF1 is a gene amplified in HGSOC and has been demonstrated to contribute to HGSOC aggressiveness and chemoresistance. The proposed study will reveal whether the mechanism of RSF1 action during normal development is also operating in overexpressed RSF1-conferred HGSOC aggressiveness and chemoresistance. New Insights Provided by the Proposed Study: The proposed study will reveal the underlying mechanism by which overexpressed RSF1 drives HGSOC aggressiveness and chemoresistance. It will form the foundation for targeted treatments of this deadly ovarian cancer subtype by disrupting the RSF1-H2Aub nucleosome interaction. Furthermore, current epigenetic drugs, with few exceptions, remain to be translated into effective therapies, largely due to their cytotoxicity and pleiotropic effects. The UAB decoy peptides specifically block the RSF1-H2Aub nucleosome interaction, eliminating the pleiotropic effects of RSF1 knockdown. The ubiquitin variants and small molecules we are characterizing may well yield drugs with therapeutic potential. Related to OCRP Vision and Mission: The immediate outcome of the proposed study is to reveal the mechanism controlling HGSOC aggressiveness and chemoresistance and to build up the foundation for targeting the RSF1 and H2Aub interaction for HGSOC treatment. The long-term implication is to develop therapeutic strategies targeting the PRC1-H2Aub-RSF1 epigenetic pathway, such as identification of small molecules that interf
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110714
Entities
People
- Hengbin Wang
Organizations
- United States Army
- University of Alabama at Birmingham