Abstract
Centrosome-localized mitotic Aurora kinase A (AURKA) facilitates G2/M events. Here we show that AURKA translocates to the nucleus and causes distinct oncogenic properties in malignant cells by enhancing breast cancer stem cell (BCSC) phenotype. Unexpectedly, this function is independent of its kinase activity. Instead, AURKA preferentially interacts with heterogeneous nuclear ribonucleoprotein K (hnRNP K) in the nucleus and acts as a transcription factor in a complex that induces a shift in MYC promoter usage and activates the MYC promoter. Blocking AURKA nuclear localization inhibits this newly discovered transactivating function of AURKA, sensitizing resistant BCSC to kinase inhibition. These findings identify a previously unknown oncogenic property of the spatially deregulated AURKA in tumorigenesis and provide a potential therapeutic opportunity to overcome kinase inhibitor resistance.
Highlights
Centrosome-localized mitotic Aurora kinase A (AURKA) facilitates G2/M events
We found that oncogenic transformation of primary mouse embryonic fibroblasts by overexpressing K-Ras (G12V mutant) or H-Ras (G12V mutant; Fig. 1c left panel) increased both cytoplasmic and nuclear AURKA expression (Fig. 1c right panel)
We found that AURKA expression induced the activity of the MYC promoter, which was more likely to be dependent on the nuclear localization of AURKA (Fig. 2f,g) than its kinase activity (Supplementary Fig. 2l)
Summary
We show that AURKA translocates to the nucleus and causes distinct oncogenic properties in malignant cells by enhancing breast cancer stem cell (BCSC) phenotype. This function is independent of its kinase activity. Blocking AURKA nuclear localization inhibits this newly discovered transactivating function of AURKA, sensitizing resistant BCSC to kinase inhibition. These findings identify a previously unknown oncogenic property of the spatially deregulated AURKA in tumorigenesis and provide a potential therapeutic opportunity to overcome kinase inhibitor resistance. 2 Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou 510080, China. The mechanisms that underlie therapeutic kinase inhibitor resistance remain elusive and require further elucidation
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