A negative feedback loop between XBP1 and Fbw7 regulates cancer development
A negative feedback loop between XBP1 and Fbw7 regulates cancer development
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DOI：
10.1038/s41389-019-0124-4
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发表时间：
2019-02-19
期刊：
影响因子：
6.2
通讯作者：
Min, Sang-Hyun
中科院分区：
文献类型：
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作者：
Chae, Unbin;Lee, Heejin;Min, Sang-Hyun
在癌症中，X-box结合蛋白（XBP 1）的激活在肿瘤发生和癌症进展中起关键作用。XBP 1在肿瘤发生发展中的转录调控机制已为人们所熟知，但其泛素化和降解的调控机制尚未阐明。在这里，我们表明，Fbw 7，SKP 1-Cullin-F-box型E3连接酶的底物识别组件，以磷酸化依赖的方式与XBP 1相互作用，并促进XBP 1泛素化和蛋白质降解。此外，Fbw 7抑制致癌途径，包括由XBP 1诱导的NF-κ B、AP 1和Myc。有趣的是，XBP 1通过NF-κ B/E2 F-1轴信号通路的反馈机制负调控Fbw 7的转录，这表明XBP 1的过表达可能导致人类癌症中Fbw 7的低水平表达。因此，Fbw 7和XBP 1之间的负反馈回路有助于调节肿瘤的发展，并且可以成为癌症新疗法的有吸引力的靶标。
In cancer, activation of X-box binding protein (XBP1) has a critical role in tumorigenesis and cancer progression. Transcriptional regulatory mechanism of XBP1 in cancer development has been well known, however, regulation of ubiquitination and degradation of XBP1 has not been elucidated yet. Here we show that Fbw7, a substrate recognition component of the SKP1-Cullin-F-box-type E3 ligase, interacts with XBP1 in a phosphorylation-dependent manner, and facilitates XBP1 ubiquitination and protein degradation. Moreover, Fbw7 inhibits oncogenic pathways including NF-kappa B, AP1, and Myc induced by XBP1. Interestingly, XBP1 negatively regulates transcription of Fbw7 via a feedback mechanism through NF-kappa B/E2F-1 axis signaling pathway, suggesting that overexpression of XBP1s may contribute to low level of Fbw7 expression in human cancers. Therefore, a negative feedback loop between Fbw7 and XBP1 contributes to the regulation of tumor development and can be an attractive target for novel therapy in cancers.