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Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis

Oncogene volume 37, pages 6212–6224 (2018)Cite this article

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Abstract

The histone methyltransferase multiple myeloma SET domain protein (MMSET/WHSC1) is highly expressed in diverse tumor types, and its expression appears to be involved in cell proliferation. In this study, we report that MMSET interacts with and methylates Aurora kinase A (AURKA). We show that MMSET-mediated methylation of AURKA induces interaction with p53 as well as enhanced kinase activity of AURKA, which results in the proteasomal degradation of p53. MMSET-mediated p53 degradation increases cell proliferation and results in oncogenic activity. Furthermore, knockdown of MMSET potently inhibits tumorigenic cells and renders them sensitive to growth inhibition by the therapeutic drug, alisertib (AURKA inhibitor). Taken together, our results suggest that MMSET is a regulator of p53 stability via methylation of AURKA in proliferating cells and might be a potential therapeutic target in solid tumors.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1A4A1008035 and NRF-2017R1A2B4004407)

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  1. Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul, 06974, Republic of Korea

    Jin Woo Park, Yun-Cheol Chae, Ji-Young Kim, Hyein Oh & Sang-Beom Seo

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  1. Jin Woo Park
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Correspondence to Sang-Beom Seo.

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Park, J.W., Chae, YC., Kim, JY. et al. Methylation of Aurora kinase A by MMSET reduces p53 stability and regulates cell proliferation and apoptosis. Oncogene 37, 6212–6224 (2018). https://doi.org/10.1038/s41388-018-0393-y

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