Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
Nat Commun. 2012;3:1072. doi: 10.1038/ncomms2074.
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.
热休克蛋白 70（HSP70）是一种进化上高度保守的分子伴侣，已知其可以通过磷酸化、泛素化和糖基化等多种方式进行翻译后修饰，但赖氨酸甲基化的生理意义尚不清楚。在这里，我们鉴定出 SETD1A 对 HSP70 的赖氨酸 561 进行二甲基化。通过免疫组织化学分析，在各种类型的人类癌症中检测到 HSP70 甲基化增强，尽管在相应的非肿瘤组织中几乎检测不到甲基化。有趣的是，甲基化的 HSP70 主要定位于癌细胞的核内，而 HSP70 蛋白的大部分位于细胞质中。核内 HSP70 以依赖于甲基化的方式直接与 Aurora 激酶 B（AURKB）相互作用，并在体外和体内促进 AURKB 活性。我们还发现，甲基化的 HSP70 在癌细胞中有促进生长的作用。我们的研究结果表明 HSP70 甲基化在人类癌症发生中起关键作用。
