title: CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1.
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.
authors.affiliation: Jinan University Institute of Tumor Pharmacology, Guangzhou 510632, China.|Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Tongzheng
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Yin
authors.affiliation: School of Life Sciences, Southwest University, Chongqing 400715, China.
authors.forename: Haoxing
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Qin
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Chenming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Respiratory Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Department of Pathology, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Yin
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: JungJin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: SeungBaek
authors.initials: S
authors.lastname: Lee
authors.affiliation: First Affiliated Hospital, Chinese PLA General Hospital, Beijing 100818, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Medical Scientist Training Program, Mayo Medical School and Mayo Graduate School, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Somaira
authors.initials: S
authors.lastname: Nowsheen
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Subspecialty General Surgery, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Boughey
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.|Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.|Key Laboratory of Arrhythmias of the Ministry of Education of China, East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D061986:MCF-7 Cells; D051379:Mice; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007976:Leupeptins; D010879:Piperazines; D011725:Pyridines; D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D010450:Endopeptidases; C484854:USP17L2 protein, human; C500026:palbociclib; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde