Histone H2A T120 Phosphorylation Promotes Oncogenic Transformation via Upregulation of Cyclin D1

Autor: Haruhiko Koseki, Yoshiaki Kodama, Satoshi Inoue, Takashi Ito, Hirofumi Mizusaki, Masanori Kato, Tomonori Hayashi, Edwin Cheung, Mitsuhiro Yoneda, Yukio Takeshima, Takeya Nakagawa, Hitoshi Aihara, Tsuyoshi Ikura, Masaya Oki, Ken-ichi Takayama, Yuko Imamura, Masamichi Doiguchi, Miki Higashi, Toshiyuki Nakayama, Hiroyuki Aburatani
Rok vydání: 2016
Předmět:
Threonine
0301 basic medicine
animal structures
Cyclin A
Protamine Kinase
Protein Serine-Threonine Kinases
Methylation
Histones
Mice
03 medical and health sciences
0302 clinical medicine
Histone H2A-T120 phosphorylation
Cell Line
Tumor
Histone methylation
Histone H2A
Animals
Drosophila Proteins
Humans
Cyclin D1
Amino Acid Sequence
Phosphorylation
Molecular Biology
Histone deacetylase 5
Sequence Homology
Amino Acid
biology
Intracellular Signaling Peptides and Proteins
Ubiquitination
Cell Biology
Chromatin
Gene Expression Regulation
Neoplastic
Cell Transformation
Neoplastic
Drosophila melanogaster
030104 developmental biology
Histone
Histone phosphorylation
030220 oncology & carcinogenesis
Histone methyltransferase
embryonic structures
biology.protein
Cancer research
Oligopeptides
Protein Processing
Post-Translational
Sequence Alignment
HeLa Cells
Signal Transduction
Zdroj: Molecular Cell. 64:176-188
ISSN: 1097-2765
DOI: 10.1016/j.molcel.2016.09.012
Popis: 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.
Databáze: OpenAIRE
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