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CDK4/6-USP51 axis regulates lung adenocarcinoma metastasis through ZEB1

Cancer Gene Therapy volume 29, pages 1181–1192 (2022)Cite this article

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Abstract

USP51 is a member of the deubiquitinase (DUB) family that participates in many pathophysiological processes. However, the aberrant expression and biological function of USP51 in cancer progression remain largely unclear. In this study, we demonstrated that USP51 is overexpressed in metastatic human lung adenocarcinoma and patients with high USP51 expression in their tumors have shorter overall survival than those with low expression of USP51. Moreover, we showed that USP51 promotes tumor metastasis and invasion through regulating ZEB1, which is a key transcriptional factor that induces the malignant progression of lung adenocarcinoma. In terms of molecular mechanism, USP51 is phosphorylated and activated by CDK4/6, thus resulting in the deubiquitination and stabilization of ZEB1 protein. Of note, we also confirmed that the expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 are significantly positively correlated in human lung adenocarcinoma samples. In conclusion, these findings revealed that the CDK4/6-USP51-ZEB1 signaling pathway is a driver of lung adenocarcinoma metastasis, which could be a potential therapeutic strategy for the treatment of malignant tumors.

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Fig. 1: USP51 is highly expressed and functionally linked to tumor metastasis in lung adenocarcinoma.
Fig. 2: USP51 regulates lung adenocarcinoma metastasis through ZEB1.
Fig. 3: USP51 deubiquitinates ZEB1.
Fig. 4: CDK4/6 phosphorylates USP51 and contributes to the degradation of ZEB1 protein.
Fig. 5: CDK4/6-induced phosphorylation of UPS51 promotes lung adenocarcinoma metastasis.
Fig. 6: P-USP51, ZEB1 and CDK4/6 activity are positively correlated in human lung adenocarcinoma patients.

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Acknowledgements

This work is supported by grants from the National Natural Science Foundation of China (No. 82172801; No. 81972454).

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Authors and Affiliations

  1. Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Medical College of Nankai University, Tianjin, 300071, China

    Jianjun Li, Xuechun Xiao, Hang Wang, Wenhao Wang, Yang Ou, Zhaoyang Wang, Huimin Jiang, Yuxin Liu & Shuang Yang

  2. Institute of Clinical Medicine, Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, 330006, Jiangxi, China

    Zhen Zhang

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  1. Jianjun Li
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Contributions

Conception and design: JL, ZZ, and SY; Development of methodology: JL, HW, YO, ZW, HJ, ZZ, and SY; Analysis and interpretation of data (for example, statistical analysis, biostatistics, computational analysis): JL, XX, WW, YL, ZZ, and SY; Writing, review of the manuscript: JL, ZZ, and SY.

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Li, J., Xiao, X., Wang, H. et al. CDK4/6-USP51 axis regulates lung adenocarcinoma metastasis through ZEB1. Cancer Gene Ther 29, 1181–1192 (2022). https://doi.org/10.1038/s41417-021-00420-7

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