Abstract 4473: The role of HBO1 in epithelial ovarian cancer

Abstract

Abstract Epithelial ovarian cancer (OC) is now the fourth leading cause of cancer death among women in the U.S and the leading cause of death in gynecological cancers. This lethality is due to both its asymptomatic nature and the lack of effective treatment strategies for advanced stage disease. OC comprises a variety of tumor types (histotypes) that differ in morphology, prognosis, etiology and molecular biology. Despite the knowledge of OC heterogeneity, current treatment strategies are very similar, and unfortunately, very ineffectual. New approaches, to inhibit OC growth and progression are therefore being sought, with few obvious targets for directed therapy. Currently, large-scale gene expression, DNA copy number and mutational screens have not been able to pinpoint new high frequency drugable targets. Epigenetic therapy conceives a whole genome approach, potentially circumventing the reliance on therapies that target infrequently mutated genes. So far in OC, most studies have focused on the inactivation of tumor suppressor genes (DNMTi, EZH2i, HDACi⋯) with mixed success, while little is known about the epigenetic activation of cancer-associated genes. Histone acetyl-transferases like GCN5, PCAF and p300 have been targeted in cancer previously, and the main purpose of this study is to assess the role of one such acetyl-transferase, Histone acetyl-transferase binding to origin of replication complex 1” (HBO1, also known as KAT7 and MYST2) in the progression of OC. HBO1 is a histone acetyltransferase (HAT) that plays important roles in diverse molecular processes including DNA replication, transcription and DNA repair. Importantly, HBO1 is overexpressed in primary cancers (breast, testis, ovarian), although the molecular basis of its role is still unclear. To better understand HBO1's role in OC, we characterized its expression in well-defined OC cell lines both at the mRNA and protein level. Observed in vitro patterns of HBO1 expression correlate well with previous observations; HBO1 is overexpressed in several OC cell lines. Interestingly, the serous histotype (both the most common and the most aggressive) generally shows the highest expression. Thus far, we have now analyzed HBO1's downstream regulatory pathways in several OC cell lines through use of siRNA knock-down coupled to microarray analysis. Comparisons of the various datasets have revealed pathways common to all cell lines studied, as well as distinction. Our approach aims to identify known epigenomic signatures that may be associated with HBO1 binding and downstream signaling which may drive differentiation toward the most advanced stages of the disease. Translating this new information through epigenetic targeting and structural inhibition may lead to novel, next-generation therapies for this most complex of disease presentations. Citation Format: Marcos Quintela. The role of HBO1 in epithelial ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4473.