FBXW2 通过泛素化 NF-κB p65 抑制乳腺癌干细胞特性、肿瘤发生和紫杉醇耐药性。
Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance.
机构信息
Department of Reproductive Medicine, Affiliated Hospital of Weifang Medical University, Weifang, PR China.
Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, PR China.
出版信息
Cell Death Differ. 2022 Feb;29(2):381-392. doi: 10.1038/s41418-021-00862-4. Epub 2021 Aug 31.
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.
F-box 和 WD 重复蛋白 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 在乳腺癌中的功能仍不清楚。在这里，我们发现核因子-κB（NF-κB）p65 是 FBXW2 的一个新底物。FBXW2 直接与 p65 结合，导致其泛素化和降解。有趣的是，p65 的 p300 乙酰化阻止了 FBXW2 诱导的 p65 泛素化。FBXW2-p65 轴是乳腺癌中 SOX2 诱导干性的关键调节因子。此外，FBXW2 通过调节体外和体内 p65 的降解来抑制乳腺癌肿瘤的生长。FBXW2 过表达消除了 p65 在体外和体内对紫杉醇耐药性的影响。此外，在 FBXW2 敲除小鼠中也证实了 FBXW2 诱导的 p65 降解。我们的研究结果确定 FBXW2 是 p65 降解的重要 E3 连接酶，这为 FBXW2 在乳腺癌中的肿瘤抑制功能提供了新的见解。
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