FBXL10 promotes ERRα protein stability and proliferation of breast cancer cells by enhancing the mono-ubiquitylation of ERRα
FBXL10 promotes ERRα protein stability and proliferation of breast cancer cells by enhancing the mono-ubiquitylation of ERRα
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FBXL10 通过增强 ERRα 的单泛素化来促进 ERRα 蛋白的稳定性和乳腺癌细胞的增殖
DOI：
10.1016/j.canlet.2021.01.007
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Wu Huijian
中科院分区：
文献类型：
--
作者：
Yang Yangyang;Li Shujing;Li Bowen;Li Yanan;Xia Kangkai;Aman Sattout;Yang Yuxi;Ahmad Bashir;Zhao Binggong;Wu Huijian
通过质谱鉴定孤儿核受体雌激素相关受体α（ERRα）与乳腺癌的相互作用伙伴，探讨ERR α在乳腺癌中的作用机制。F-box和富含亮氨酸的重复蛋白10（FBXL 10）调节各种生理过程，可能与乳腺癌中的ERRα相互作用。本研究旨在探讨FBXL 10和ERRα之间的相互作用及其在乳腺癌中的蛋白表达和相关性。力学研究表明，FBXL 10通过减少其多聚泛素化和促进其单泛素化来稳定ERRα蛋白水平。通过报告基因试验和ERRα靶基因检查，证实了由于FBXL 10增加了ERRα的蛋白水平，因此ERRα的转录活性增加。FBXL 10还增加了ERRα在其靶基因启动子区的富集。在功能上，FBXL 10促进ERRα/过氧化物酶体增殖物激活受体γ共激活因子1 β（PGC 1 β）介导的乳腺癌细胞体外和体内增殖和肿瘤发生。我们的研究结果揭示了ERRα的单泛素化和蛋白质稳定性与FBXL 10功能相互作用的分子机制。此外，FBXL 10和ERRα调节乳腺癌细胞的增殖和成瘤的新的调节轴被建立。
The underlying mechanism of orphan nuclear receptor estrogen-related receptor α (ERRα) in breast cancer was investigated by identifying its interaction partners using mass spectrometry. F-box and leucine-rich repeat protein 10 (FBXL10), which modulates various physiological processes, may interact with ERRα in breast cancer. Here, we investigated the interaction between FBXL10 and ERRα, and their protein expression and correlation in breast cancer. Mechanical studies revealed that FBXL10 stabilized ERRα protein levels by reducing its poly-ubiquitylation and promoting its mono-ubiquitylation. The reporter gene assay and examination of ERRα target genes validated the increased transcriptional activity of ERRα due to its increased protein levels by FBXL10. FBXL10 also increased ERRα enrichment at the promoter region of its target genes. Functionally, FBXL10 facilitated the ERRα/peroxisome proliferator-activated receptor gamma coactivator 1 β (PGC1β)-mediated proliferation and tumorigenesis of breast cancer cellsin vitroandin vivo. Our results uncovered a molecular mechanism linking the mono-ubiquitylation and protein stability of ERRα to functional interaction with FBXL10. Moreover, a novel regulatory axis of FBXL10 and ERRα regulating the proliferation and tumorigenesis of breast cancer cells was established.