CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1.
CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1.
复制标题
CDK4/6 依赖性 DUB3 激活通过 SNAIL1 调节癌症转移。
DOI：
10.1038/ncomms13923
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发表时间：
2017-01-09
影响因子：
16.6
通讯作者：
Lou Z
中科院分区：
文献类型：
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作者：
Liu T;Yu J;Deng M;Yin Y;Zhang H;Luo K;Qin B;Li Y;Wu C;Ren T;Han Y;Yin P;Kim J;Lee S;Lin J;Zhang L;Zhang J;Nowsheen S;Wang L;Boughey J;Goetz MP;Yuan J;Lou Z
肿瘤转移，即癌细胞从原始肿瘤部位扩散，随后在远处器官生长继发性肿瘤，是癌症相关死亡的主要原因，目前仍知之甚少。在这里，我们证明了在三阴性乳腺癌模型中抑制CDK 4/6阻断乳腺肿瘤转移，而不影响肿瘤生长。从机制上讲，我们确定了一种去泛素化酶DUB 3作为CDK 4/6的靶点; CDK 4/6介导的DUB 3活化对于去泛素化和稳定SNAIL 1是必不可少的，SNAIL 1是促进上皮-间质转化和乳腺癌转移的关键因素。总的来说，我们的研究确立了CDK 4/6-DUB 3轴作为乳腺癌转移的重要调节机制，并为乳腺癌转移治疗中的潜在治疗干预提供了理论基础。SNAIL的过表达赋予肿瘤细胞与肿瘤进展相关的癌干细胞样特征。在这里，作者表明，抑制CDK 4/6通过靶向DUB 3阻断三阴性乳腺癌中的肿瘤转移，DUB 3反过来去泛素化并稳定SNAIL 1。
Tumour metastasis, the spread of cancer cells from the original tumour site followed by growth of secondary tumours at distant organs, is the primary cause of cancer-related deaths and remains poorly understood. Here we demonstrate that inhibition of CDK4/6 blocks breast tumour metastasis in the triple-negative breast cancer model, without affecting tumour growth. Mechanistically, we identify a deubiquitinase, DUB3, as a target of CDK4/6; CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a key factor promoting epithelial–mesenchymal transition and breast cancer metastasis. Overall, our study establishes the CDK4/6–DUB3 axis as an important regulatory mechanism of breast cancer metastasis and provides a rationale for potential therapeutic interventions in the treatment of breast cancer metastasis. Overexpression of SNAIL confers tumour cells with cancer stem-like characteristics associated with tumour progression. Here the authors show that inhibition of CDK4/6 blocks tumour metastasis in triple negative breast cancer by targeting DUB3 which in turns deubiquitinates and stabilises SNAIL1.