Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, 350116, Fujian, China.
Institute of Oceanography, Minjiang University, Fuzhou, 350116, Fujian, China.
Oncogene. 2020 Mar;39(13):2741-2755. doi: 10.1038/s41388-020-1179-6. Epub 2020 Jan 31.
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.
黑色素瘤转移的关键分子和潜在机制仍知之甚少。通过使用相对和绝对定量同位素标签（iTRAQ）蛋白质组学筛选、对患者样本的探测、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。通过获得和丧失功能的方法，发现 WDR74 促进了体外细胞增殖、抗凋亡和侵袭行为。此外，WDR74 促进了体内黑色素瘤的生长和转移。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 可以作为临床预防和治疗黑色素瘤的候选靶点。
