FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells.
FOXM1 recruits nuclear Aurora kinase A to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells.
复制标题
FOXM1 招募核极光激酶 A 参与乳腺癌干细胞自我更新所必需的正反馈回路。
作者：
Yang N;Wang C;Wang Z;Zona S;Lin SX;Wang X;Yan M;Zheng FM;Li SS;Xu B;Bella L;Yong JS;Lam EW;Liu Q
大量证据表明，乳腺癌的发生、复发和耐药性是由乳腺癌干细胞（BCSC）支持的。最近，我们报道了极光激酶A（AURKA）在BCSC中的新作用，作为诱导c-Myc癌蛋白的反式激活辅助因子。然而，核AURKA在BCSCs中的作用方式和转录网络仍然未知。在这里，我们报告说，核AURKA可以招募叉头盒亚类M1（FOXM 1）作为一个辅助因子，以激酶非依赖性的方式反式激活FOXM 1靶基因。此外，我们发现AURKA和FOXM 1参与了一个紧密耦合的正反馈回路，以增强BCSC表型。事实上，激酶死亡的AURKA可以通过Forkhead反应元件有效地反式激活FOXM 1启动子，而FOXM 1可以以类似的方式在转录水平上激活AURKA表达。一致地，乳腺癌患者样品描绘了FOXM 1和AURKA的表达水平之间的强且显著的相关性。此外，FOXM 1和AURKA对于维持BCSC群体是必不可少的。最后，我们证明了AURKA抑制剂AKI 603和FOXM 1抑制剂硫链丝菌素协同作用，分别抑制细胞质AURKA活性和破坏细胞核AURKA/FOXM 1正反馈环，从而更有效地抑制BCSC的致瘤性和自我更新能力。总的来说，我们的研究揭示了AURKA和FOXM 1之间以前未知的紧密耦合的正反馈信号循环，这对BCSC自我更新至关重要。值得注意的是，我们的数据揭示了一种新的潜在治疗策略，用于靶向细胞质和细胞核AURKA功能，以有效消除BCSC，从而克服乳腺癌和耐药性。
Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by Forkhead box subclass M1 (FOXM1) as a co-factor to transactivate FOXM1 target genes in a kinase-independent manner. In addition, we show that AURKA and FOXM1 participate in a tightly coupled positive feedback loop to enhance BCSC phenotype. Indeed, kinase-dead AURKA can effectively transactivate the FOXM1 promoter through a Forkhead response element, whereas FOXM1 can activate AURKA expression at the transcriptional level in a similar manner. Consistently, breast cancer patient samples portrayed a strong and significant correlation between the expression levels of FOXM1 and AURKA. Moreover, both FOXM1 and AURKA were essential for maintaining the BCSC population. Finally, we demonstrated that the AURKA inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic AURKA activity and disrupt the nuclear AURKA/FOXM1-positive feedback loop, respectively, resulting in a more effective inhibition of the tumorigenicity and self-renewal ability of BCSCs. Collectively, our study uncovers a previously unknown tightly coupled positive feedback signalling loop between AURKA and FOXM1, crucial for BCSC self-renewal. Remarkably, our data reveal a novel potential therapeutic strategy for targeting both the cytoplasmic and nuclear AURKA function to effectively eliminate BCSCs, so as to overcome both breast cancer and drug resistance.