SCF(JFK) is a bona fide E3 ligase for ING4 and a potent promoter of the angiogenesis and metastasis of breast cancer

Genes & Development
Ruorong YanYongfeng Shang

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.

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Citations

Jan 25, 2016·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Shuping YuanYongzhong Hou
May 31, 2016·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Muzammal HussainGuang-Biao Zhou
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Jan 8, 2020·International Journal of Molecular Sciences·Scott BangManabu Kurokawa
May 1, 2021·Cancers·Karine Jacquet, Olivier Binda
Jun 12, 2021·EMBO Reports·Lin HeLuyang Sun
Aug 3, 2021·Frontiers in Cell and Developmental Biology·Ziran YangLuyang Sun

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