Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival
Polo-like Kinase-1 Regulates Myc Stabilization and Activates a Feedforward Circuit Promoting Tumor Cell Survival
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Polo 样激酶-1 调节 Myc 稳定性并激活前馈回路，促进肿瘤细胞存活。
DOI：
10.1016/j.molcel.2016.09.016
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发表时间：
2016-11-03
期刊：
影响因子：
16
通讯作者：
Qing, Guoliang
中科院分区：
文献类型：
--
作者：
Xiao, Daibiao;Yue, Ming;Qing, Guoliang
人类癌症中MYCN的扩增预示着不良的预后和对治疗的抵抗。然而，直接针对MYCN编码的蛋白质N-Myc的药理策略仍然难以捉摸。在这里，我们确定了Polo-like kinase1(PLK1)和N-Myc相互激活的分子机制。PLK1特异性地与SCF Fbw7泛素连接酶结合，使其磷酸化，促进其自身泛素化和蛋白酶体降解，对抗Fbw7介导的N-Myc和其他底物的降解，包括细胞周期蛋白E和MCL1。稳定的N-Myc反过来直接激活PLK1转录，构成一个正前馈调控环，加强Myc调控的致癌程序。PLK1抑制剂优先诱导神经母细胞瘤和小细胞肺癌MYCN扩增的肿瘤细胞的有效凋亡，并协同增强Bcl2拮抗剂的治疗效果。这些发现揭示了PLK1-Fbw7-Myc信号通路是肿瘤发生的基础，并验证了PLK1抑制剂单独或与Bcl2拮抗剂一起作为治疗MYC过表达癌症的潜在有效疗法。
MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF Fbw7 ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers.