PDF(Pubmed)
Abstract：
Tumor metastasis is the major cause of breast cancer morbidity and mortality. It has been reported that the F-box protein FBXO3 functions as an E3 ubiquitin ligase in regulating various biological processes, including host autoimmune, antiviral innate immunity, and inflammatory response. However, the role of FBXO3 in tumor metastasis remains elusive. We have previously shown that ΔNp63α is a common inhibitory target in oncogene-induced cell motility and tumor metastasis. In this study, we show that FBXO3 plays a vital role in PI3K-mediated breast cancer metastasis independent of its E3 ligase activity and ΔNp63α in breast cancer cells and in mouse. FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis. Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation. Furthermore, p110αH1047R facilitates the phosphorylation and stabilization of FBXO3 in an ERK1-dependent manner. Knockdown of either FBXO3 or USP4 leads to significant inhibition of PI3K-induced breast cancer metastasis. Clinically, elevated expression of p110α/FBXO3/USP4/Twist1 is associated with poor overall survival (OS) and recurrence-free survival (RFS) of breast cancer patients. Taken together, this study reveals that the FBXO3-USP4-Twist1 axis is pivotal in PI3K-mediated breast tumor metastasis and that FBXO3/USP4 may be potential therapeutic targets for breast cancer treatment.
摘要：
肿瘤转移是乳腺癌发病和死亡的主要原因。据报道，F-box蛋白FBXO3作为E3泛素连接酶在调节各种生物过程中起作用。包括宿主自身免疫，抗病毒先天性免疫，和炎症反应。然而,FBXO3在肿瘤转移中的作用仍然难以捉摸。我们先前已经表明，ΔNp63α是癌基因诱导的细胞运动和肿瘤转移中的常见抑制靶标。在这项研究中,我们表明，FBXO3在PI3K介导的乳腺癌转移中起着至关重要的作用，而与乳腺癌细胞和小鼠中的E3连接酶活性和ΔNp63α无关。FBXO3可以结合并稳定USP4，导致Twist1蛋白稳定并增加乳腺癌细胞迁移和肿瘤转移。机械上,FBXO3破坏USP4和天冬氨酰氨基肽酶（DNPEP）之间的相互作用，从而保护USP4免受DNPEP介导的降解。此外，p110αH1047R以ERK1依赖性方式促进FBXO3的磷酸化和稳定。FBXO3或USP4的敲除导致PI3K诱导的乳腺癌转移的显著抑制。临床上,p110α/FBXO3/USP4/Twist1表达升高与乳腺癌患者总生存期(OS)和无复发生存期(RFS)较差相关.一起来看,这项研究表明,FBXO3-USP4-Twist1轴在PI3K介导的乳腺肿瘤转移中起着关键作用,FBXO3/USP4可能是乳腺癌治疗的潜在治疗靶点.
