title: Enhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B.
abstract: Although heat-shock protein 70 (HSP70), an evolutionarily highly conserved molecular chaperone, is known to be post-translationally modified in various ways such as phosphorylation, ubiquitination and glycosylation, physiological significance of lysine methylation has never been elucidated. Here we identify dimethylation of HSP70 at Lys-561 by SETD1A. Enhanced HSP70 methylation was detected in various types of human cancer by immunohistochemical analysis, although the methylation was barely detectable in corresponding non-neoplastic tissues. Interestingly, methylated HSP70 predominantly localizes to the nucleus of cancer cells, whereas most of the HSP70 protein locates to the cytoplasm. Nuclear HSP70 directly interacts with Aurora kinase B (AURKB) in a methylation-dependent manner and promotes AURKB activity in vitro and in vivo. We also find that methylated HSP70 has a growth-promoting effect in cancer cells. Our findings demonstrate a crucial role of HSP70 methylation in human carcinogenesis.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Shimazu
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Shinya
authors.initials: S
authors.lastname: Hayami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ito
authors.forename: Ken
authors.initials: K
authors.lastname: Masuda
authors.forename: Noriko
authors.initials: N
authors.lastname: Ikawa
authors.forename: Helen I
authors.initials: HI
authors.lastname: Field
authors.forename: Eiju
authors.initials: E
authors.lastname: Tsuchiya
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ohnuma
authors.forename: Bruce A J
authors.initials: BA
authors.lastname: Ponder
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ryuji
authors.initials: R
authors.lastname: Hamamoto
mesh_terms: D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D015153:Blotting, Western; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008239:Lysine; D008745:Methylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D018840:HSP70 Heat-Shock Proteins; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D008239:Lysine