CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
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DOI：
10.1038/s41392-020-0118-x
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发表时间：
2020-03-11
影响因子：
39.3
通讯作者：
Yang, Shuang
中科院分区：
文献类型：
--
作者：
Zhang, Zhen;Li, Jianjun;Yang, Shuang
肿瘤转移是癌症相关死亡的最常见原因，但对其了解甚少。转录因子锌指E-box binding homeobox 1（ZEB 1）参与上皮细胞向间充质细胞转化（EMT）并在肿瘤转移中起关键作用。然而，ZEB 1的翻译后修饰的潜在机制仍然在很大程度上未知。在此，我们证明了特异性抑制CDK 4/6能够通过使ZEB 1蛋白在体外和体内不稳定来阻断乳腺癌的肿瘤转移。从机制上讲，我们确定去泛素化酶USP 51是CDK 4/6的真正靶标。USP 51被CDK 4/6磷酸化和激活是去泛素化和稳定ZEB 1所必需的。此外，我们发现转移性人乳腺癌样品中p-RB（CDK 4/6活性的指标）、p-USP 51和ZEB 1的表达之间存在强正相关性。值得注意的是，p-RB、p-USP 51和ZEB 1的高表达与不良临床结局显著相关。综上所述，我们的研究结果提供了证据表明CDK 4/6-USP 51-ZEB 1轴在乳腺癌转移中起着关键作用，并可能成为治疗晚期人类癌症的可行治疗靶点。
Tumor metastasis is the most common cause of cancer-related deaths, yet it remains poorly understood. The transcription factor zinc-finger E-box binding homeobox 1 (ZEB1) is involved in the epithelial-to-mesenchymal transition (EMT) and plays a pivotal role in tumor metastasis. However, the underlying mechanisms of the posttranslational modification of ZEB1 remain largely unknown. Herein, we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in vivo. Mechanistically, we determined that the deubiquitinase USP51 is a bona fide target of CDK4/6. The phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ZEB1. Moreover, we found a strong positive correlation between the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in metastatic human breast cancer samples. Notably, the high expression of p-RB, p-USP51, and ZEB1 was significantly correlated with a poor clinical outcome. Taken together, our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.