title: The hypoxia-inducible epigenetic regulators Jmjd1a and G9a provide a mechanistic link between angiogenesis and tumor growth.
abstract: Hypoxia promotes stem cell maintenance and tumor progression, but it remains unclear how it regulates long-term adaptation toward these processes. We reveal a striking downregulation of the hypoxia-inducible histone H3 lysine 9 (H3K9) demethylase JMJD1A as a hallmark of clinical human germ cell-derived tumors, such as seminomas, yolk sac tumors, and embryonal carcinomas. Jmjd1a was not essential for stem cell self-renewal but played a crucial role as a tumor suppressor in opposition to the hypoxia-regulated oncogenic H3K9 methyltransferase G9a. Importantly, loss of Jmjd1a resulted in increased tumor growth, whereas loss of G9a produced smaller tumors. Pharmacological inhibition of G9a also resulted in attenuation of tumor growth, offering a novel therapeutic strategy for germ cell-derived tumors. Finally, Jmjd1a and G9a drive mutually opposing expression of the antiangiogenic factor genes Robo4, Igfbp4, Notch4, and Tfpi accompanied by changes in H3K9 methylation status. Thus, we demonstrate a novel mechanistic link whereby hypoxia-regulated epigenetic changes are instrumental for the control of tumor growth through coordinated dysregulation of antiangiogenic gene expression.
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore junueda@biken.osaka-u.ac.jp Lorenz.Poellinger@ki.se.
authors: Jun
authors: J
authors: Ueda
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Jolene Caifeng
authors: JC
authors: Ho
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Kian Leong
authors: KL
authors: Lee
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Shojiro
authors: S
authors: Kitajima
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Henry
authors: H
authors: Yang
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Wendi
authors: W
authors: Sun
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Noriko
authors: N
authors: Fukuhara
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Norazean
authors: N
authors: Zaiden
authors: Xenograft Cancer Models Facility, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Shing Leng
authors: SL
authors: Chan
authors: Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors: Makoto
authors: M
authors: Tachibana
authors: Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors: Yoichi
authors: Y
authors: Shinkai
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore.
authors: Hiroyuki
authors: H
authors: Kato
authors: Cancer Biology Program, Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore, Republic of Singapore Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden junueda@biken.osaka-u.ac.jp Lorenz.Poellinger@ki.se.
authors: Lorenz
authors: L
authors: Poellinger
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000235:genetics*; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013234:Stem Cells / Q000378:metabolism*; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D046888:Tissue Array Analysis
chemical_list: D006649:Histocompatibility Antigens; D056484:Jumonji Domain-Containing Histone Demethylases