title: Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via down-regulating angiogenesis.
abstract: Histone demethylase JHDM1D (also known as KDM7A) modifies the level of methylation in histone and participates in epigenetic gene regulation; however, the role of JHDM1D in tumor progression is unknown. Here, we show that JHDM1D plays a tumor-suppressive role by regulating angiogenesis. Expression of JHDM1D was increased in mouse and human cancer cells under long-term nutrient starvation in vitro. Expression of JHDM1D mRNA was increased within avascular tumor tissue at the preangiogenic switch, along with increased expression of angiogenesis-regulating genes such as Vegf-A. Stable expression of JHDM1D cDNA or siRNA silencing of JHDM1D in cancer cells did not affect cell proliferation, anchorage-independent cell growth, or cell cycle progression in vitro. Notably, JHDM1D-expressing mouse melanoma (B16) and human cervical carcinoma (HeLa) cells exhibited significantly slower tumor growth in vivo compared with the original cells. This reduction in tumor growth was associated with decreased formation of CD31(+) blood vessels and reduced infiltration of CD11b(+) macrophage linage cells into tumor tissues. Expression of multiple angiogenic factors such as VEGF-B and angiopoietins was decreased in tumor xenografts of JHDM1D-expressing B16 and HeLa cells. Our results provide evidence that increased JHDM1D expression suppressed tumor growth by down-regulating angiogenesis under nutrient starvation.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine and Dentistry,  Tokyo Medical and Dental University, 1-5-45 Bunkyo-ku, Yushima, Tokyo 113-8519,  Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Osawa
authors.forename: Masashi
authors.initials: M
authors.lastname: Muramatsu
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Rika
authors.initials: R
authors.lastname: Tsuchida
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.forename: Masabumi
authors.initials: M
authors.lastname: Shibuya
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003470:Culture Media / Q000737:chemistry; D018450:Disease Progression; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D003470:Culture Media; D042461:Vascular Endothelial Growth Factor A; D056484:Jumonji Domain-Containing Histone Demethylases; C547782:KDM7 protein, mouse; C548973:KDM7A protein, human