title: The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: L
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: T
authors.initials: T
authors.lastname: Karnik
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: G
authors.initials: G
authors.lastname: Tadros
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mau
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ma
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Medical Scholars Program, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: J
authors.initials: J
authors.lastname: New
authors.affiliation: Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Louie
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gunewardena
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: O W
authors.initials: OW
authors.lastname: Tawfik
authors.affiliation: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: J
authors.initials: J
authors.lastname: Chien
authors.affiliation: Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Roby
authors.affiliation: Department of Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA.|Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Krieg
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics*; D051379:Mice; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D010537:Peritoneum / Q000473:pathology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human