title: Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages.
abstract: Antiangiogenic strategies can be effective for cancer therapy, but like all therapies resistance poses a major clinical challenge. Hypoxia and nutrient starvation select for aggressive qualities that may render tumors resistant to antiangiogenic attack. Here, we show that hypoxia and nutrient starvation cooperate to drive tumor aggressiveness through epigenetic regulation of the histone demethylase JMJD1A (JHDM2A; KDM3A). In cancer cells rendered resistant to long-term hypoxia and nutrient starvation, we documented a stimulation of AKT phosphorylation, cell morphologic changes, cell migration, invasion, and anchorage-independent growth in culture. These qualities associated in vivo with increased angiogenesis and infiltration of macrophages into tumor tissues. Through expression microarray analysis, we identified a cluster of functional drivers such as VEGFA, FGF18, and JMJD1A, the latter which was upregulated in vitro under conditions of hypoxia and nutrient starvation and in vivo before activation of the angiogenic switch or the prerefractory phase of antiangiogenic therapy. JMJD1A inhibition suppressed tumor growth by downregulating angiogenesis and macrophage infiltration, by suppressing expression of FGF2, HGF, and ANG2. Notably, JMJD1A inhibition enhanced the antitumor effects of the anti-VEGF compound bevacizumab and the VEGFR/KDR inhibitor sunitinib. Our results form the foundation of a strategy to attack hypoxia- and nutrient starvation-resistant cancer cells as an approach to leverage antiangiogenic treatments and limit resistance to them.
authors.affiliation: Laboratory for Vascular Biology, Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. osawa@lsbm.org
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Osawa
authors.forename: Rika
authors.initials: R
authors.lastname: Tsuchida
authors.forename: Masashi
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suehiro
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kanki
authors.forename: Youichiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Yuasa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000502:physiology; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000209:etiology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; D040262:Receptors, Vascular Endothelial Growth Factor