Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance
Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance
复制标题
FbxW2泛素化NF-κB p65抑制乳腺癌干细胞、肿瘤发生和紫杉醇耐药
DOI：
10.1038/s41418-021-00862-4
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发表时间：
2021-08-31
影响因子：
12.4
通讯作者：
Yu, Zhenhai
中科院分区：
文献类型：
--
作者：
Ren, Chune;Han, Xue;Yu, Zhenhai
F-box和WD-重复包含蛋白2（FBXW 2）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，FBXW 2在乳腺癌中的功能仍然未知。在这里，我们发现核因子-κ B（NF-κ B）p65是FBXW 2的一种新底物。FBXW 2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FBXW 2诱导的p65泛素化。FBXW 2-p65轴是SOX 2诱导的乳腺癌干性的关键调节因子。此外，FBXW 2在体外和体内通过调节p65降解来抑制乳腺肿瘤生长。FBXW 2过表达在体外和体内消除了p65对紫杉醇耐药性的影响。此外，FBXW 2诱导的p65降解也在FBXW 2敲除小鼠中得到证实。我们的研究结果确定FBXW 2作为p65降解的重要E3连接酶，这为FBXW 2在乳腺癌中的肿瘤抑制功能提供了见解。
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-kappa B) 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.