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USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis

Oncogene volume 38, pages 2405–2419 (2019)Cite this article

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A Correction to this article was published on 03 February 2022

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Abstract

Metastatic progression is the main cause of mortality in breast cancer, necessitating the determination of the molecular events driving this process for the development of new therapeutic approaches. Here, we demonstrate that hyperactivation of the deubiquitinase USP1 contributes to breast cancer metastasis. Upregulated USP1 expression in primary breast cancer specimens correlates with metastatic progression and poor prognosis in breast cancer patients. USP1 enhances the expression of a number of pro-metastatic genes in breast cancer cells, promotes cell migration and invasion in vitro, and facilitates lung metastasis of breast cancer cells. Moreover, USP1-mediated deubiquitination and stabilization of KPNA2 are revealed as the downstream events crucial for USP1-pro-metastatic function. Most importantly, pharmacological intervention of USP1 function by pimozide or ML323 significantly represses breast cancer metastasis in mice, suggesting a rationale for using USP1 inhibitors for treatment of patients with breast cancer. Taken together, our results establish USP1 as a promoter of breast cancer metastasis and provide evidence for the potential practice of USP1 targeting in the treatment of breast cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81572293, 31770976, and 81672359), Natural Science Foundation of Shanghai (18ZR1436800), the State Key Laboratory of Oncogenes and Related Genes (91–1705, 91-17-11), and Shanghai Cancer Institute (SB18-07).

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  1. These authors contributed equally: Aihui Ma, Ming Tang

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  1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 200032, Shanghai, China

    Aihui Ma, Ming Tang, Li Zhang, Boshi Wang, Zhaojuan Yang, Yun Liu, Guiqin Xu, Lin Wu, Tiantian Jing, Xiaoli Xu, Shengli Yang & Yongzhong Liu

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Correspondence to Yongzhong Liu.

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Ma, A., Tang, M., Zhang, L. et al. USP1 inhibition destabilizes KPNA2 and suppresses breast cancer metastasis. Oncogene 38, 2405–2419 (2019). https://doi.org/10.1038/s41388-018-0590-8

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