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WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway

Abstract

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.

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Fig. 1: WDR74 is upregulated in metastatic melanoma compared with that in primary melanoma.
Fig. 2: WDR74 promotes cell proliferation and cell cycle progression in A375 cells in vitro.
Fig. 3: WDR74 is associated with apoptosis resistance in A375 cells in vitro.
Fig. 4: WDR74 impacts on metastasis-related capacities in A375 cells in vitro.
Fig. 5: WDR74 regulates the RPL5–MDM2–p53 pathway.
Fig. 6: WDR74 contributes to tumor growth and distant metastasis of melanoma in nude mice.

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Acknowledgements

We thank Gang Liu and Yingying Zhang for technical help in gene construct, Rong Xiang in pathology examination assistance.

Funding

This work was supported by the grants from National Natural Science Foundation of China (81961138017, 81773063, U1505225); Ministry of Science and Technology of China (2015CB931804).

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Li, Y., Zhou, Y., Li, B. et al. WDR74 modulates melanoma tumorigenesis and metastasis through the RPL5–MDM2–p53 pathway. Oncogene 39, 2741–2755 (2020). https://doi.org/10.1038/s41388-020-1179-6

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