title: Deregulation of the histone demethylase JMJD2A is involved in human carcinogenesis through regulation of the G(1)/S transition.
abstract: Although a number of JmjC-containing histone demethylases have been identified and biochemically characterized, pathological roles of their dysfunction in human disease such as cancer have not been well elucidated. Here, we report the Jumonji domain containing 2A (JMJD2A) is integral to proliferation of cancer cells. Quantitative real-time PCR analysis revealed higher expression of JMJD2A in clinical bladder cancer tissues than in corresponding non-neoplastic tissues (P<0.0001). Immunohistochemical analysis also showed positive staining for JMJD2A in 288 out of 403 lung cancer cases, whereas no staining was observed in lung normal tissues. Suppression of JMJD2A expression in lung and bladder cancer cells overexpressing this gene, using specific siRNAs, inhibited incorporation of BrdU and resulted in significant suppression of cell growth. Furthermore, JMJD2A appears to directly transactivate the expression of some tumor associated proteins including ADAM12 through the regulation of histone H3K9 methylation. As expression levels of JMJD2A are low in normal tissues, it may be feasible to develop specific inhibitors targeting the enzyme as anti-tumor agents which should have a minimal risk of adverse reaction.
authors.affiliation: Laboratory of Genome Technology, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Tokyo 108-8639, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kogure
authors.forename: Masashi
authors.initials: M
authors.lastname: Takawa
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Hayashi
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Takaaki
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Masanori
authors.initials: M
authors.lastname: Sugiyama
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Atomi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005260:Female; D016193:G1 Phase; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000378:metabolism; D016196:S Phase; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human