CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.
CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels.
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DOI：
10.1158/1940-6207.capr-10-0360
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Zhang JY
中科院分区：
文献类型：
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作者：
Miliani de Marval P;Lutfeali S;Jin JY;Leshin B;Selim MA;Zhang JY
CYLD已被认为是一种肿瘤抑制因子，因为它与多种类型的表皮肿瘤和一系列其他癌症具有显性遗传联系。CYLD控制皮肤癌的分子机制尚不清楚。在这里，我们证明了k14驱动的与患者相关且催化缺陷的CYLD截断突变体（CYLDm）的表皮表达使小鼠在DMBA/ tpa刺激下对皮肤肿瘤的发展敏感。转基因小鼠的肿瘤容易发生恶性进展和淋巴结转移，JNK和下游c-Jun和c-Fos蛋白的激活增加。最重要的是，局部应用药理学JNK抑制剂可显著减少转基因小鼠的肿瘤发展和消除转移。进一步与这些动物数据一致，CYLDm在人鳞状细胞癌（SCC）细胞系A431中的外源性表达，以ap1依赖的方式显著增强细胞生长、迁移和皮下肿瘤生长。相比之下，野生型CYLD的表达抑制SCC肿瘤发生和AP1功能。最重要的是，CYLDm不仅增加了JNK的激活，还诱导了c-Jun和c-Fos上k63泛素化的上调，导致AP1持续激活。我们的研究结果揭示了c-Jun和c-Fos是CYLD的新靶点，并强调CYLD通过在多个水平上阻断JNK/AP1信号通路来控制表皮肿瘤的发生。
CYLD has been recognized as a tumor suppressor due to its dominant genetic linkage to multiple types of epidermal tumors and a range of other cancers. The molecular mechanisms governing CYLD control of skin cancer are still unclear. Here, we demonstrated that K14-driven epidermal expression of a patient relevant and catalytically deficient CYLD truncation mutant (CYLDm) sensitized mice to skin tumor development in response to DMBA/TPA-challenge. Tumors developed on transgenic mice were prone to malignant progression and lymph node metastasis, and displayed increased activation of JNK and the downstream c-Jun and c-Fos proteins. Most importantly, topical application of a pharmacological JNK inhibitor significantly reduced tumor development and abolished metastasis in the transgenic mice. Further in line with these animal data, exogenous expression of CYLDm in A431, a human squamous cell carcinoma (SCC) cell line, markedly enhanced cell growth, migration and subcutaneous tumor growth in an AP1-depdendent manner. In contrast, expression of the wild type CYLD inhibited SCC tumorigenesis and AP1 function. Most importantly, CYLDm not only increased JNK activation but also induced an upregulation of K63-ubiquitination on both c-Jun and c-Fos, leading to sustained AP1 activation. Our findings uncovered c-Jun and c-Fos as novel CYLD-targets and underscore that CYLD controls epidermal tumorigenesis through blocking the JNK/AP1 signaling pathway at multiple levels.