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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.

SUBMITTER: Cho HS

PROVIDER: S-EPMC3658001 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Enhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B.

Cho Hyun-Soo HS Shimazu Tadahiro T Toyokawa Gouji G Daigo Yataro Y Maehara Yoshihiko Y Hayami Shinya S Ito Akihiro A Masuda Ken K Ikawa Noriko N Field Helen I HI Tsuchiya Eiju E Ohnuma Shin-ichi S Ponder Bruce A J BA Yoshida Minoru M Nakamura Yusuke Y Hamamoto Ryuji R

Nature communications 20120101

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 dete ...[more]

PMID: 22990868

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Project description:Purpose:Receptor-interacting protein kinase 1 (RIPK1) is an important upstream regulator of multiple cell signaling pathways including inflammatory signals. RIPK1 is reported to be closely associated with the prognostic implications of cancer, especially epithelial tumors. But its role in proliferation and lymphangiogenesis in cholangiocarcinoma (CCA) remains unclear and requires further investigation. Patients and methods:Expression of RIPK1 in human CCA tissues and CCA cell lines (QBC939, HUH28 and CCPL-1) was measured using qPCR, immunoblotting and immunohistochemistry. Silencing of RIPK1 was achieved by transduction of CCA cells via lentiviral plasmids (LV3-H1/GFP&Puro) encapsulating RIPK1 shRNA (LV-shRIPK1) or negative control shRNA (LV-shNC), and puromycin was used to select stable colonies. Proliferation and lymphangiogenesis were assessed in vitro by CCK-8 and matrigel-based tube formation assays, respectively. Activity of the activation protein-1 (AP-1) was evaluated by double-luciferase reporter gene assay. Protein expression of JNK, P38MAPK, ERK1/2, AP-1, P-AP-1, E-cadherin, N-cadherin and vascular endothelial growth factor-C (VEGF-C) was measured by immunoblotting or ELISA. An orthotopic CCA model in null mice was generated by transplanting QBC939 LV-shRIPK1, LV-shNC and control cells to further evaluate the role of RIPK1 on lymphangiogenesis in vivo. Immunohistochemistry was utilized to evaluate the expression of RIPK1 and VEGF-C, and tumor lymphatic vessels in the CCA model mice. Results:Upregulated expression of RIPK1 in CCA tissues was closely related to tumor size, lymph node metastasis and poor prognosis. RIPK1 promoted proliferation and lymphangiogenesis in CCA cells, and regulated the activation of JNK and P38MAPK-mediated AP-1/VEGF-C pathway. Finally, in vivo animal experiments in the orthotopic CCA mouse model further confirmed the function of RIPK1 in lymphangiogenesis. Conclusion:This is the first report demonstrating the role of RIPK1 in proliferation and lymphangiogenesis through the MAPK (JNK and P38MAPK)- AP-1 pathway in CCA.

Dataset Information

Enhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B.

Publications

Enhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B.

Similar Datasets

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