The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer
| Autor: | Wilson, C, Qiu, L, Hong, Y, Karnik, T, Tadros, G, Mau, B, Ma, T, Mu, Y, New, J, Louie, RJ, Gunewardena, S, Godwin, AK, Tawfik, OW, Chien, J, Roby, KF, Krieg, AJ |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Jumonji Domain-Containing Histone Demethylases
endocrine system diseases Clinical Sciences Oncology and Carcinogenesis Cell Line Promoter Regions Mice Rare Diseases Genetic Genetics 2.1 Biological and endogenous factors Animals Humans Oncology & Carcinogenesis Peritoneal Neoplasms Cancer Cell Proliferation Ovarian Neoplasms Neoplastic Tumor Prognosis Xenograft Model Antitumor Assays female genital diseases and pregnancy complications Ovarian Cancer Neoplasm Proteins Neoplasm Recurrence Gene Expression Regulation Local Female Peritoneum Biomarkers |
| Zdroj: | Oncogene, vol 36, iss 18 |
| Popis: | Epithelial ovarian cancer (EOC) has poor prognosis and rapid recurrence because of widespread dissemination of peritoneal metastases at diagnosis. Multiple pathways contribute to the aggressiveness of ovarian cancer, including hypoxic signaling mechanisms. In this study, we have determined that the hypoxia-inducible histone demethylase KDM4B is expressed in ∼60% of EOC tumors assayed, including primary and matched metastatic tumors. Expression of KDM4B in tumors is positively correlated with expression of the tumor hypoxia marker CA-IX, and is robustly induced in EOC cell lines exposed to hypoxia. KDM4B regulates expression of metastatic genes and pathways, and loss of KDM4B increases H3K9 trimethylation at the promoters of target genes like LOXL2, LCN2 and PDGFB. Suppressing KDM4B inhibits ovarian cancer cell invasion, migration and spheroid formation in vitro. KDM4B also regulates seeding and growth of peritoneal tumors in vivo, where its expression corresponds to hypoxic regions. This is the first demonstration that a Jumonji-domain histone demethylase regulates cellular processes required for peritoneal dissemination of cancer cells, one of the predominant factors affecting prognosis of EOC. The pathways regulated by KDM4B may present novel opportunities to develop combinatorial therapies to improve existing therapies for EOC patients. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|