CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1

Tongzheng Liu, Jia Yu, Min Deng, Yujiao Yin, Haoxing Zhang, Kuntian Luo, Bo Qin, Yunhui Li, Chenming Wu, Tao Ren, Yang Han, Peng Yin, JungJin Kim, SeungBaek Lee, Jing Lin, Lizhi Zhang, Jun Zhang, Somaira Nowsheen, Liewei Wang, Judy Boughey, Matthew P. Goetz, Jian Yuan () and Zhenkun Lou ()
Additional contact information
Tongzheng Liu: Jinan University Institute of Tumor Pharmacology
Jia Yu: Mayo Clinic
Min Deng: Mayo Clinic
Yujiao Yin: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Haoxing Zhang: School of Life Sciences, Southwest University
Kuntian Luo: Mayo Clinic
Bo Qin: Mayo Clinic
Yunhui Li: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Chenming Wu: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine
Tao Ren: East Hospital, Tongji University School of Medicine
Yang Han: East Hospital, Tongji University School of Medicine
Peng Yin: Mayo Clinic
JungJin Kim: Mayo Clinic
SeungBaek Lee: Mayo Clinic
Jing Lin: First Affiliated Hospital, Chinese PLA General Hospital
Lizhi Zhang: Mayo Clinic
Jun Zhang: Mayo Clinic
Somaira Nowsheen: Medical Scientist Training Program, Mayo Medical School and Mayo Graduate School, Mayo Clinic
Liewei Wang: Mayo Clinic
Judy Boughey: Mayo Clinic
Matthew P. Goetz: Mayo Clinic
Jian Yuan: Mayo Clinic
Zhenkun Lou: Mayo Clinic

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms13923

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