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Aurora B induces epithelial–mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis

Oncogene volume 39, pages 2550–2567 (2020)Cite this article

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Abstract

Aurora B is a serine/threonine kinase that has been implicated in regulating cell proliferation in distinct cancers, including breast cancer. Here we show that Aurora B expression is elevated in basal-like breast cancer (BLBC) compared with other breast cancer subtypes. This high level of expression seems to correlate with poor metastasis-free survival and relapse-free survival in affected patients. Mechanistically, we show that elevated Aurora B expression in breast cancer cells activates AKT/GSK3β to stabilize Snail1 protein, a master regulator of epithelial–mesenchymal transition (EMT), leading to EMT induction in a kinase-dependent manner. Conversely, Aurora B knock down by short-hairpin RNAs (shRNAs) suppresses AKT/GSK3β/Snail1 signaling, reverses EMT and reduces breast cancer metastatic potential in vitro and in vivo. Finally, we identified a specific OCT4 phosphorylation site (T343) responsible for mediating Aurora B-induced AKT/GSK3β/Snail1 signaling and EMT that could be attenuated by Aurora B kinase inhibitor treatment. These findings support that Aurora B induces EMT to promote breast cancer metastasis via OCT4/AKT/GSK3β/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.

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Fig. 1: Elevated Aurora B expression in breast cancer is associated with aggressive disease.
Fig. 2: Aurora B knockdown reverses the basal-like breast cancer cell mesenchymal phenotype.
Fig. 3: Aurora B knockdown suppresses basal-like breast cancer tumor metastasis.
Fig. 4: Aurora B expression stabilizes Snail1 protein.
Fig. 5: AKT/GSK3β activation is essential for Aurora B-induced Snail1 stability, which is dependent upon Aurora B kinase activity.
Fig. 6: OCT4 phosphorylation at T343 is a critical mediator for Aurora B-induced EMT.
Fig. 7: Aurora B inhibitor inhibits Aurora B-induced EMT and metastasis of TNBC.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81672912, 81972753, and 81502537), the Science and Technology Program of Guangdong Province, China (2017B030301016 and 2016A030310128), the Shenzhen Basic Research Program (JCYJ20170818143630465, JCYJ20170818101638620, and JCYJ20180507182203049) and the Shenzhen Peacock Innovation Team Project (KQTD20140630100658078). The authors would like to thank Dr Jessica Tamanini (Shenzhen University, ETediting) for editing the paper prior to submission. We acknowledge the help of the Instrumental Analysis Center of Shenzhen University (Xili Campus) for technical assistance.

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  1. Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Pharmacology, Base for International Science and Technology Cooperation: Carson Cancer Stem Cell Vaccines R&D Center, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, 518055, China

    Jianchao Zhang, Xinxin Lin, Liufeng Wu & Suping Zhang

  2. State Key Laboratory of Oncology in South China, Department of Medical Oncology, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China

    Jia-Jia Huang & Wen-Qi Jiang

  3. Moores UCSD Cancer Center, University of California, 9310 Athena Circle, La Jolla, San Diego, CA, 92093, USA

    Thomas J. Kipps & Suping Zhang

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Zhang, J., Lin, X., Wu, L. et al. Aurora B induces epithelial–mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis. Oncogene 39, 2550–2567 (2020). https://doi.org/10.1038/s41388-020-1165-z

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