title: SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer.
abstract: Loss of function/dysregulation of inhibitor of growth 4 (ING4) and hyperactivation of NF-κB are frequent events in many types of human malignancies. However, the molecular mechanisms underlying these remarkable aberrations are not understood. Here, we report that ING4 is physically associated with JFK. We demonstrated that JFK targets ING4 for ubiquitination and degradation through assembly of an Skp1-Cul1-F-box (SCF) complex. We showed that JFK-mediated ING4 destabilization leads to the hyperactivation of the canonical NF-κB pathway and promotes angiogenesis and metastasis of breast cancer. Significantly, the expression of JFK is markedly up-regulated in breast cancer, and the level of JFK is negatively correlated with that of ING4 and positively correlated with an aggressive clinical behavior of breast carcinomas. Our study identified SCF(JFK) as a bona fide E3 ligase for ING4 and unraveled the JFK-ING4-NF-κB axis as an important player in the development and progression of breast cancer, supporting the pursuit of JFK as a potential target for breast cancer intervention.
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Ruorong
authors: R
authors: Yan
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Lin
authors: L
authors: He
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Beijing 100142, China;
authors: Zhongwu
authors: Z
authors: Li
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Xiao
authors: X
authors: Han
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Jing
authors: J
authors: Liang
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Wenzhe
authors: W
authors: Si
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Zhe
authors: Z
authors: Chen
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Lei
authors: L
authors: Li
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Guojia
authors: G
authors: Xie
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Wanjin
authors: W
authors: Li
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
authors: Peiyan
authors: P
authors: Wang
authors: Laboratory of Molecular Imaging, Peking University Health Science Center, Beijing 100191, China;
authors: Liandi
authors: L
authors: Lei
authors: Department of Anatomy, Histology, and Embryology, Peking University Health Science Center, Beijing 100191, China;
authors: Hongquan
authors: H
authors: Zhang
authors: Department of Pathology, Peking University Health Science Center, Beijing 100191, China;
authors: Fei
authors: F
authors: Pei
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University School of Oncology, Beijing 100142, China;
authors: Dengfeng
authors: D
authors: Cao
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; yshang@hsc.pku.edu.cn yshang@tmu.edu.cn luyang_sun@hsc.pku.edu.cn.
authors: Luyang
authors: L
authors: Sun
authors: Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China; 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, China yshang@hsc.pku.edu.cn yshang@tmu.edu.cn luyang_sun@hsc.pku.edu.cn.
authors: Yongfeng
authors: Y
authors: Shang
mesh_terms: D001943:Breast Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000503:physiopathology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D061986:MCF-7 Cells; D046912:Multiprotein Complexes; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000235:genetics; D059748:Proteolysis; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; C542109:FBXO42 protein, human; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D046912:Multiprotein Complexes; D016328:NF-kappa B; D025521:Tumor Suppressor Proteins
keywords: E3 ligase; ING4; JFK; angiogenesis; breast cancer; metastasis