β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer
β-Trcp ubiquitin ligase and RSK2 kinase-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer
复制标题
β-Trcp 泛素连接酶和 RSK2 激酶介导的 FOXN2 降解促进肺癌的肿瘤发生和放射抗性
DOI：
10.1038/s41418-017-0055-6
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发表时间：
2018-08-01
影响因子：
12.4
通讯作者：
Xu, Shuangbing
中科院分区：
文献类型：
--
作者：
Ma, Jia;Lu, Yanwei;Xu, Shuangbing
FOXN 2是叉头盒转录因子的成员，其异常表达已在几种类型的癌症中被发现。然而，FOXN 2失调在肿瘤发生中的潜在机制在很大程度上仍然未知。在这里，我们发现FOXN 2与β-Trcp泛素连接酶和RSK 2激酶结合并被其泛素化以进行降解。此外，我们证明了保守的DSGYAS基序中的Ser 365和Ser 369位点对于β-Trcp和RSK 2降解FOXN 2是至关重要的。此外，功能获得和功能丧失研究表明，FOXN 2在体外和体内损害细胞增殖，并增强肺癌的放射敏感性。重要的是，β-Trcp介导和RSK 2介导的FOXN 2降解促进肺癌细胞的肿瘤发生和放射抗性。总的来说，我们的研究揭示了FOXN 2的一种新的翻译后修饰，并表明FOXN 2可能是肺癌的潜在治疗和放射增敏靶点。
Aberrant expression of FOXN2, a member of the Forkhead box transcription factors, has been found in several types of cancer. However, the underlying mechanisms of FOXN2 deregulation in tumorigenesis remain largely unknown. Here, we find that FOXN2 binds to and is ubiquitinated by β-Trcp ubiquitin ligase and RSK2 kinase for degradation. Furthermore, we demonstrate that the Ser365 and Ser369 sites in a conserved DSGYAS motif are critical for the degradation of FOXN2 by β-Trcp and RSK2. Moreover, gain-of-function and loss-of-function studies show that FOXN2 impairs cell proliferation in vitro and in vivo and enhances the radiosensitivity of lung cancer. Importantly, β-Trcp-mediated and RSK2-mediated degradation of FOXN2 promotes tumorigenesis and radioresistance in lung cancer cells. Collectively, our study reveals a novel post-translational modification of FOXN2 and suggests that FOXN2 may be a potential therapeutic and radiosensitization target for lung cancer.