UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2
UFBP1, a key component in ufmylation, enhances drug sensitivity by promoting proteasomal degradation of oxidative stress-response transcription factor Nrf2
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UFBP1 是 ufmylation 的关键成分，通过促进氧化应激反应转录因子 Nrf2 的蛋白酶体降解来增强药物敏感性
DOI：
10.1038/s41388-020-01551-1
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发表时间：
2020-11-20
期刊：
影响因子：
8
通讯作者：
Xu, Guoqiang
中科院分区：
文献类型：
--
作者：
Hu, Zhanhong;Wang, Xiaohui;Xu, Guoqiang
UFM1偶联系统中的关键成分UFM1结合和PCI结构域含蛋白1 （UFBP1）调节许多生物过程。最近有研究表明，低UFBP1蛋白水平与胃癌患者预后较差有关。然而，它如何响应胃癌对化疗药物的敏感性及其潜在的分子机制尚不清楚。在这里，我们发现UFBP1的高表达增加了晚期胃癌患者接受铂类化疗的无进展生存期。基于细胞系的研究发现，UFBP1表达增强，而eufbp1敲低可减弱胃癌细胞对顺铂的敏感性。基于silac的高通量定量蛋白质组学分析显示，UFBP1显著下调醛酮还原酶1Cs （AKR1Cs）的蛋白水平。流式细胞术分析显示，顺铂治疗后，UFBP1表达增加，eufbp1敲低可降低活性氧。我们进一步发现，UFBP1降低了akr1c的基因表达和主要氧化应激反应转录因子Nrf2（核因子-红细胞-2相关因子2）的转录活性。详细的机制研究表明，UFBP1促进Nrf2上k48连接的多泛素链的形成，从而增强其蛋白酶体介导的降解。体外和体内基因耗尽和药理激活实验表明，UFBP1通过Nrf2/AKR1C轴增强胃癌细胞对顺铂的敏感性。总的来说，本研究发现了一种新的基于铂类化疗的胃癌患者预后生物标志物，并阐明了其潜在的分子机制，这可能有助于未来的个性化化疗。
The key component in the UFM1 conjugation system, UFM1-binding and PCI domain-containing protein 1 (UFBP1), regulates many biological processes. Recently it has been shown that low UFBP1 protein level is associated with the worse outcome of gastric cancer patients. However, how it responses to the sensitivity of gastric cancer to chemotherapy drugs and the underlying molecular mechanism remain elusive. Here, we discovered that high UFBP1 expression increases the progression-free survival of advanced gastric cancer patients treated with platinum-based chemotherapy. Cell-line based studies unveiled that UFBP1 expression enhances whileUFBP1knockdown attenuates the sensitivity of gastric cancer cells to cisplatin. High-throughput SILAC-based quantitative proteomic analysis revealed that the protein level of aldo-keto reductase 1Cs (AKR1Cs) is significantly downregulated by UFBP1. Flow cytometry analysis showed that UFBP1 expression increases whileUFBP1knockdown reduces reactive oxygen species upon cisplatin treatment. We further disclosed that UFBP1 attenuates the gene expression ofAKR1Cs and the transcription activity of the master oxidative stress-response transcription factor Nrf2 (nuclear factor erythroid-2-related factor 2). Detailed mechanistic studies manifested that UFBP1 promotes the formation of K48-linked polyubiquitin chains on Nrf2 and thus augments its proteasome-mediated degradation. Experiments using genetic depletion and pharmacological activation in vitro and in vivo demonstrated that UFBP1 enhances the sensitivity of gastric cancer cells to cisplatin through the Nrf2/AKR1C axis. Overall, this work discovered a novel prognostic biomarker for gastric cancer patients treated with platinum-based chemotherapy and elucidated the underlying molecular mechanism, which may benefit to future personalized chemotherapy.