The F-box and WD-repeat-containing protein 2 (FBXW2) plays a crucial role as an E3 ligase in regulating tumorigenesis. However, the functions of FBXW2 in breast cancer are still unknown. Here, we find that nuclear factor-kB (NF-κB) p65 is a new substrate of FBXW2. FBXW2 directly binds to p65, leading to its ubiquitination and degradation. Interestingly, p300 acetylation of p65 blocks FBXW2 induced p65 ubiquitination. FBXW2-p65 axis is a crucial regulator of SOX2-induced stemness in breast cancer. Moreover, FBXW2 inhibits breast tumor growth by regulating p65 degradation in vitro and in vivo. FBXW2 overexpression abrogates the effects of p65 on paclitaxel resistance in vitro and in vivo. Furthermore, FBXW2 induced p65 degradation is also confirmed in FBXW2-knockout mice. Our results identify FBXW2 as an important E3 ligase for p65 degradation, which provide insights into the tumor suppressor functions of FBXW2 in breast cancer.

含有 F-box 和 WD 重复的蛋白 2 (FBXW2) 作为 E3 连接酶在调节肿瘤发生中起着至关重要的作用。然而，FBXW2在乳腺癌中的作用仍然未知。在这里，我们发现核因子-kB (NF-κB) p65 是 FBXW2 的新底物。FBXW2 直接与 p65 结合，导致其泛素化和降解。有趣的是，p65 的 p300 乙酰化阻断了 FBXW2 诱导的 p65 泛素化。FBXW2-p65 轴是 SOX2 诱导的乳腺癌干性的关键调节因子。此外，FBXW2 通过在体外和体内调节 p65 降解来抑制乳腺肿瘤的生长。FBXW2 过表达消除了 p65 在体外和体内对紫杉醇抗性的影响。此外，FBXW2 诱导的 p65 降解也在 FBXW2 敲除小鼠中得到证实。我们的结果将 FBXW2 确定为 p65 降解的重要 E3 连接酶，