title: Histone H2A T120 Phosphorylation Promotes Oncogenic Transformation via Upregulation of Cyclin D1.
abstract: How deregulation of chromatin modifiers causes malignancies is of general interest. Here, we show that histone H2A T120 is phosphorylated in human cancer cell lines and demonstrate that this phosphorylation is catalyzed by hVRK1. Cyclin D1 was one of ten genes downregulated upon VRK1 knockdown in two different cell lines and showed loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In vitro, H2A T120 phosphorylation and H2A K119 ubiquitylation are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, expression of a phosphomimetic H2A T120D increased H3 K4 methylation. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. These results suggest that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene expression, including upregulated cyclin D1, which promotes oncogenic transformation.
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Aihara
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Mizusaki
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Yoneda
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Kato
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Doiguchi
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Imamura
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Higashi
authors.affiliation: Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.affiliation: Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima 732-0815, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima 732-0815, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Oki
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Genome Institute of Singapore, Singapore 138672, Singapore.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Takayama
authors.affiliation: RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.affiliation: Department of Anti-Aging Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan; Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: Second Department of Pathology, Hiroshima University School of Medicine, Hiroshima 734-8553, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Takeshima
authors.affiliation: Nagasaki University School of Medicine, Nagasaki 852-8523, Japan. Electronic address: tito@nagasaki-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D006656:Protamine Kinase / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013912:Threonine / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D002843:Chromatin; D029721:Drosophila Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D019938:Cyclin D1; D013912:Threonine; C085706:FLAG peptide; C506651:Ball protein, Drosophila; D006656:Protamine Kinase; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human
keywords: H2A; NHK-1; VRK1; cyclin D1; histone modification; phosphorylation; ubiquitylation