Jinan University Institute of Tumor Pharmacology, Guangzhou 510632, China.
Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Nat Commun. 2017 Jan 9;8:13923. doi: 10.1038/ncomms13923.
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.
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出继发性肿瘤，是癌症相关死亡的主要原因，但目前仍未被充分理解。在这里，我们证明 CDK4/6 的抑制作用可阻止三阴性乳腺癌模型中的乳腺癌转移，而不影响肿瘤生长。从机制上讲，我们确定去泛素化酶 DUB3 是 CDK4/6 的靶标；CDK4/6 介导的 DUB3 激活对于去泛素化和稳定 SNAIL1 至关重要，SNAIL1 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 CDK4/6-DUB3 轴作为乳腺癌转移的一个重要调控机制，并为治疗乳腺癌转移的潜在治疗干预提供了理论依据。
