WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5-MDM2-p53 pathway
WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5-MDM2-p53 pathway
复制标题
DOI：
10.1038/s41388-020-1179-6
复制
发表时间：
2020-01-31
期刊：
影响因子：
8
通讯作者：
Jia, Lee
中科院分区：
文献类型：
--
作者：
Li, Yumei;Zhou, Yu;Jia, Lee
黑色素瘤转移的关键分子和潜在机制仍然知之甚少。使用等压标记进行相对和绝对定量(ITRAQ)蛋白质组筛选、患者样本探测、功能验证和机制验证，我们确定了WD重复蛋白74(WDR74)在黑色素瘤进展和转移中的重要作用。通过获得和失去功能的方法，WDR74被发现在体外促进细胞增殖、抗凋亡和攻击行为。此外，WDR74还促进了黑色素瘤的体内生长和转移。从机制上讲，WDR74调节RPL5蛋白水平，从而调节MDM2，并隔离MDM2对p53的泛素化降解。我们的研究首次揭示了WDR74在黑色素瘤进展中的致癌作用以及WDR74对RPL5-MDM2-P53通路的调节作用。总之，WDR74可以作为临床上预防和治疗黑色素瘤的候选靶点。
The key molecules and underlying mechanisms of melanoma metastasis remain poorly understood. Using isobaric tag for relative and absolute quantitation (iTRAQ) proteomic screening, probing of patients' samples, functional verification, and mechanistic validation, we identified the important role of the WD repeat-containing protein 74 (WDR74) in melanoma progression and metastasis. Through gain- and loss-of-function approaches, WDR74 was found to promote cell proliferation, apoptosis resistance, and aggressive behavior in vitro. Moreover, WDR74 contributed to melanoma growth and metastasis in vivo. Mechanistically, WDR74 modulates RPL5 protein levels and consequently regulates MDM2 and insulates the ubiquitination degradation of p53 by MDM2. Our study is the first to reveal the oncogenic role of WDR74 in melanoma progression and the regulatory effect of WDR74 on the RPL5-MDM2-p53 pathway. Collectively, WDR74 can serve as a candidate target for the prevention and treatment of melanoma in the clinic.