Author:
Yan Ruorong,He Lin,Li Zhongwu,Han Xiao,Liang Jing,Si Wenzhe,Chen Zhe,Li Lei,Xie Guojia,Li Wanjin,Wang Peiyan,Lei Liandi,Zhang Hongquan,Pei Fei,Cao Dengfeng,Sun Luyang,Shang Yongfeng
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 SCFJFK 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.
Funder
National Natural Science Foundation of China
Ministry of Science and Technology of China
Publisher
Cold Spring Harbor Laboratory
Subject
Developmental Biology,Genetics
Cited by
33 articles.
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