title: 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.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Feimeng
authors.identifier: http://orcid.org/0000-0001-8793-6677
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.|Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan Road II, Guangzhou 510080, China.
authors.forename: Caifeng
authors.initials: C
authors.lastname: Yue
authors.affiliation: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.affiliation: The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China.
authors.forename: Zijie
authors.initials: Z
authors.lastname: Long
authors.affiliation: The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China.
authors.forename: Wanshou
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Cancer Hospital/Cancer Institute, College of Life Sciences and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.|Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, 6 HSUEH-SHIH Road, Taichung 40402, Taiwan.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou; Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian 116044, China.|The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou 510630, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D006801:Humans; D056004:Molecular Dynamics Simulation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034622:RNA Interference; D014407:Tumor Cells, Cultured
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D064096:Aurora Kinase A