Abstract
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.
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Funding
The study was supported by research grants from the National Natural Science Foundation of China (Grant no. 81972489 and 82003201), the National Natural Science Foundation of Shandong Province (Grant no. ZR2020YQ58 and ZR2020QH255), Taishan Scholar Program of Shandong Province (Grant no. tsqn202103113), Shandong Province College Science and Technology Plan Project (Grant no. J17KA254), Projects of medical and health technology development program in Shandong province (Grant no. 2018WS057).
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CR, XH, CL, and TY performed experiments and analyzed data. PQ and YS provided access to material and facilities and contributed reagents. ZY designed, supervised the project, and wrote the manuscript.
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The procedures related to human subjects were approved by the Ethics Committee of Weifang Medical University. Animal experiments were performed according to the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals, and were approved by the ethics committee of Weifang Medical University (Weifang, China).
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Ren, C., Han, X., Lu, C. et al. Ubiquitination of NF-κB p65 by FBXW2 suppresses breast cancer stemness, tumorigenesis, and paclitaxel resistance. Cell Death Differ 29, 381–392 (2022). https://doi.org/10.1038/s41418-021-00862-4
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DOI: https://doi.org/10.1038/s41418-021-00862-4
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