Nuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype.

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.

• Authors: Feimeng Zheng, Caifeng Yue, Guohui Li, Bin He, Wei Cheng, Xi Wang, Min Yan, Zijie Long, Wanshou Qiu, Zhongyu Yuan, Jie Xu, Bing Liu, Qian Shi, Eric W-F Lam, Mien-Chie Hung, Quentin Liu
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 10180 (Jan 19 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 26782714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-myc
• Aurora Kinase A

Topics

• Aurora Kinase A (metabolism)
• Biological Transport (genetics, physiology)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Chromatin Immunoprecipitation
• Flow Cytometry
• Humans
• Molecular Dynamics Simulation
• Neoplastic Stem Cells (metabolism)
• Promoter Regions, Genetic (genetics)
• Proto-Oncogene Proteins c-myc (genetics)
• RNA Interference
• Tumor Cells, Cultured