Aurora B induces epithelial-mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis
Aurora B induces epithelial-mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis
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DOI：
10.1038/s41388-020-1165-z
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发表时间：
2020-01-29
期刊：
影响因子：
8
通讯作者：
Zhang, Suping
中科院分区：
文献类型：
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作者：
Zhang, Jianchao;Lin, Xinxin;Zhang, Suping
Aurora B是一种丝氨酸/苏氨酸激酶，参与调节包括乳腺癌在内的多种癌症的细胞增殖。本研究表明，与其他乳腺癌亚型相比，基底样乳腺癌（BLBC）中Aurora B的表达升高。这种高水平的表达似乎与受影响患者的无转移生存和无复发生存有关。在机制上，我们发现乳腺癌细胞中Aurora B表达的升高激活AKT/GSK3 β来稳定Snail1蛋白，Snail1蛋白是上皮-间质转化（EMT）的主要调节因子，导致EMT以激酶依赖的方式诱导。相反，短发卡rna （shRNAs）敲低Aurora B可抑制AKT/GSK3 β /Snail1信号，逆转EMT，降低乳腺癌在体内和体外的转移潜力。最后，我们确定了一个特定的OCT4磷酸化位点（T343），负责介导极光B诱导的AKT/GSK3 β /Snail1信号传导和EMT，可以通过极光B激酶抑制剂治疗减弱。这些发现支持Aurora B通过OCT4/AKT/GSK3 β /Snail1信号通路诱导EMT促进乳腺癌转移。药物抑制Aurora B可能是乳腺癌转移患者的潜在有效治疗方法。
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/GSK3 beta 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/GSK3 beta/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/GSK3 beta/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/GSK3 beta/Snail1 signaling. Pharmacologic Aurora B inhibition might be a potential effective treatment for breast cancer patients with metastatic disease.