FOXC2 regulates the G2/M transition of stem cell-rich breast cancer cells and sensitizes them to PLK1 inhibition.
FOXC2 regulates the G2/M transition of stem cell-rich breast cancer cells and sensitizes them to PLK1 inhibition.
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DOI：
10.1038/srep23070
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发表时间：
2016-04-11
影响因子：
4.6
通讯作者：
Mani SA
中科院分区：
文献类型：
--
作者：
Pietilä M;Vijay GV;Soundararajan R;Yu X;Symmans WF;Sphyris N;Mani SA
具有干细胞特性的癌细胞（CSC）支持三阴性乳腺癌（TNBC）的化疗耐药性和高治疗失败率。尽管已知CSC增殖较慢，但它们对G2/M激酶抑制剂如polo样激酶1（PLK 1）敏感。了解CSC的细胞周期调控机制将有助于更有效地靶向这些细胞。在这里，我们确定了一个新的作用，转录因子FOXC 2，这是主要在CSC中表达，在CSC富集乳腺癌细胞的细胞周期的调节。我们证明FOXC 2的表达是以细胞周期依赖性的方式调节的，FOXC 2蛋白水平在G2期积累，并在有丝分裂过程中迅速下降。CSC富集的TNBC细胞中F0 XC 2的敲低延迟有丝分裂进入，而不显著影响这些细胞的总体增殖速率。此外，PLK 1活性对于FOXC 2蛋白稳定性是重要的，因为PLK 1抑制降低FOXC 2蛋白水平。事实上，表达FOXC 2的CSC富集的TNBC细胞对PLK 1抑制敏感。总的来说，我们的研究结果证明了FOXC 2作为G2/M转换调节剂的新作用，并阐明了观察到的CSC富集的乳腺癌细胞对PLK 1抑制剂敏感的原因。
Cancer cells with stem cell properties (CSCs) underpin the chemotherapy resistance and high therapeutic failure of triple-negative breast cancers (TNBCs). Even though CSCs are known to proliferate more slowly, they are sensitive to inhibitors of G2/M kinases such as polo-like kinase 1 (PLK1). Understanding the cell cycle regulatory mechanisms of CSCs will help target these cells more efficiently. Herein, we identify a novel role for the transcription factor FOXC2, which is mostly expressed in CSCs, in the regulation of cell cycle of CSC-enriched breast cancer cells. We demonstrate that FOXC2 expression is regulated in a cell cycle-dependent manner, with FOXC2 protein levels accumulating in G2, and rapidly decreasing during mitosis. Knockdown of FOXC2 in CSC-enriched TNBC cells delays mitotic entry without significantly affecting the overall proliferation rate of these cells. Moreover, PLK1 activity is important for FOXC2 protein stability, since PLK1 inhibition reduces FOXC2 protein levels. Indeed, FOXC2 expressing CSC-enriched TNBC cells are sensitive to PLK1 inhibition. Collectively, our findings demonstrate a novel role for FOXC2 as a regulator of the G2/M transition and elucidate the reason for the observed sensitivity of CSC-enriched breast cancer cells to PLK1 inhibitor.