FBXO3 stabilizes USP4 and Twist1 to promote PI3K-mediated breast cancer metastasis

• DOI: 10.1371/journal.pbio.3002446
• Publication Date: 2023-12-22T18:43:18Z
• Authors: Jing Xu; Rongtian Guo; Nasi Wen; Luping Li; Yong Yi; Jingzhen Chen; Zongyu He; Jian Yang; Zhi-Xiong Jim Xiao; Mengmeng Niu
• Keywords: CA 15-3

Tumor metastasis is the major cause of breast cancer morbidity and mortality. It has been reported that F-box protein FBXO3 functions as an E3 ubiquitin ligase in regulating various biological processes, including host autoimmune, antiviral innate immunity, inflammatory response. However, role tumor remains elusive. We have previously shown ΔNp63α a common inhibitory target oncogene-induced cell motility metastasis. In this study, we show plays vital PI3K-mediated independent its activity cells mouse. can bind to stabilize USP4, leading Twist1 stabilization increased migration Mechanistically, disrupts interaction between USP4 aspartyl aminopeptidase (DNPEP), thereby protecting from DNPEP-mediated degradation. Furthermore, p110α H1047R facilitates phosphorylation ERK1-dependent manner. Knockdown either or leads significant inhibition PI3K-induced Clinically, elevated expression p110α/FBXO3/USP4/Twist1 associated with poor overall survival (OS) recurrence-free (RFS) patients. Taken together, study reveals FBXO3-USP4-Twist1 axis pivotal FBXO3/USP4 may be potential therapeutic targets for treatment.