IDENTIFICATION AND CHARACTERIZATION OF PATHWAYS REGULATED BY KDM4B IN OVARIAN CANCER

Abstract

KDM4B is a hypoxia-inducible, histone lysine demethylase responsible for primarily demethylating H3K9 and H3K36. This enzyme has been implicated in the literature as a contributor to tumorigenesis in many solid tumor models. Multiple factors contribute to the aggressiveness of ovarian cancer, including hypoxia-induced mechanisms. Establishing the tumorigenic mechanisms regulated by KDM4B provide novel epigenetic links between the hypoxic tumor microenvironment and Epithelial Ovarian Cancer (EOC) progression. This body of work established the in vitro and in vivo relevance of KDM4B in EOC, connecting expression to increased tumorigenesis. KDM4B is expressed in patient primary and metastatic tumors, correlating with hypoxic regions identified by CA-IX. Additionally, KDM4B is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes in a demethylase-dependent manner, including LOXL2, LCN2, and PDGFB. KDM4B expression correlates with increased ovarian cancer cell invasion, migration and attachment-free growth in vitro. Intraperitoneal xenograft models demonstrated KDM4B expression corresponded with increased peritoneal dissemination in vivo. Further mechanistic analysis has identified a possible link between KDM4B expression and another epigenetic regulator ARID5B. Functional analysis demonstrates KDM4B participates in secretion of factors contributing to metastasis and tumor progression. 3-Dimensional in vitro functional analysis suggests KDM4B contributes to increased spheroid invasion on Type I Collagen. This project highlights some of the first studies demonstrating that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of EOC. The following observations provide additional knowledge regarding KDM4B activity and its influence in EOC models. These findings provide a better understanding of KDM4B, its activity, and the role it plays in regulating the epigenetic landscape in tumors. The mechanistic and functional pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients.