THE HISTONE DEMETHYLASE KDM4B CONTRIBUTES TO THE PERITONEAL DISSEMINATION OF OVARIAN CANCER

Abstract

Solid tumors contain hypoxic regions due to their unchecked proliferation. This hypoxic microenvironment induces cancer cell metastasis and angiogenesis to promote tumor survival. The hypoxia-inducible factors (HIFs) are the primary regulators of the hypoxic response, inducing genes involved in important tumor progression pathways. The lysine (K)-specific demethylase KDM4B is a direct target of HIF, creating an intriguing link between the hypoxic tumor microenvironment and downstream gene expression beyond the direct actions of HIF stabilization. The findings that hypoxia-inducible KDM4B overexpression occurs in multiple cancer types suggest a general KDM4B function in these cancers. However, our current knowledge on KDM4B function in each cancer type seems to rely on tissue-specific pathways. In a microarray analysis using transient knockdown of KDM4B, we identified a set of potential KDM4B targets with clear associations to tumor cell growth, migration, and metastasis. Microarray data from HCT116 colon carcinoma, SKOV3ip.1 ovarian cancer and RCC4 renal cell carcinoma cells identified numerous genes specifically regulated in each cell type, as well as 16 common targets shared by all three cell lines. Through Ingenuity Pathway Analysis, we found that KDM4B also regulated different pathways under different oxygen conditions. In general, KDM4B regulated proliferative genes in normoxia, and metastatic genes in hypoxia. We have also demonstrated that KDM4B regulated these target genes by binding and demethylating near the promoter regions of these genes. Our findings suggest that KDM4B regulates pathways specific to each cancer type and tumor microenvironment to support cancer cell survival. Hypoxia has been linked to poor prognosis of epithelial ovarian cancer (EOC), likely through regulating genes that contribute to the widespread dissemination of peritoneal metastases observed in late-stage diagnosis. In this study, we have shown that KDM4B is expressed in high grade serous adenocarcinoma and EOC cell lines, especially in hypoxia. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B is also crucial for seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. Thus, KDM4B is a potent contributor to the seeding and growth of peritoneal tumors, one of the predominant factors affecting prognosis of EOC.