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The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis

Oncogene volume 40, pages 5482–5494 (2021)Cite this article

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Abstract

K-RAS mutation and molecular alterations of its surrogates function essentially in lung tumorigenesis and malignant progression. However, it remains elusive how tumor-promoting and deleterious events downstream of K-RAS signaling are coordinated in lung tumorigenesis. Here, we show that USP16, a deubiquitinase involved in various biological processes, functions as a promoter for the development of K-RAS-driven lung tumor. Usp16 deletion significantly attenuates K-rasG12D-mutation-induced lung tumorigenesis in mice. USP16 upregulation upon RAS activation averts reactive oxygen species (ROS)-induced p38 activation that would otherwise detrimentally influence the survival and proliferation of tumor cells. In addition, USP16 interacts with and deubiquitinates JAK1, and thereby promoting lung tumor growth by augmenting JAK1 signaling. Therefore, our results reveal that USP16 functions critically in the K-RAS-driven lung tumorigenesis through modulating the strength of p38 and JAK1 signaling.

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Fig. 1: USP16 induction contributes to K-rasG12D-driven lung tumorigenesis in mice.
Fig. 2: USP16 deficiency impairs tumorigencity of K-RAS-activated cells.
Fig. 3: USP16 regulates ROS generation and inhibits cell apoptosis via its deubiquitinase activity.
Fig. 4: p38 activation underlies USP16 deficiency-mediated inhibition of tumor growth.
Fig. 5: USP16 interacts with and deubiquitinates JAK1.
Fig. 6: USP16 coordinates JAK1 and p38 signaling in tumor cells.

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Code availability

RNAseq data from NCI-H23 and MEF cells, generated in this study, have been uploaded to the NCBI gene expression omnibus (GEO) with the accession code GSE160388 and GSE160485, respectively.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81802746, 81572694, and 81972579), and the Natural Science Foundation of Shanghai (20ZR1454100).

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  1. These authors contributed equally: Guiqin Xu, Zhaojuan Yang, Yizong Ding.

Authors and Affiliations

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

    Guiqin Xu, Zhaojuan Yang, Yun Liu, Li Zhang, Boshi Wang, Ming Tang, Tiantian Jing, Zehong Chen, Lvzhu Xiang, Chen Xu & Yongzhong Liu

  2. Department of Thoracic Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yizong Ding, Yujie Fu & Xiaojing Zhao

  3. Shanghai Jiao Tong University School of Biomedical Engineering, Shanghai, China

    Kun Jiao & Xiaoli Xu

  4. Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, People’s Republic of China

    Weilin Jin

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Contributions

G.X. and Y.Z.L. defined the project and designed the experiments. G.X. and Z.Y. carried out most of the experiments and analyzed data. Y.D., Y.L., L.Z., M.T., T.J., K.J., X.X., Z.C., L.X., and C.X. participated in experiment conduction. G.X. and B.W. performed bioinformatics analysis. Y.D., Y.F., X.Z., and W.J. provided with technical or material supports. G.X. and Y.Z.L. wrote and edited the paper.

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Correspondence to Yongzhong Liu.

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Xu, G., Yang, Z., Ding, Y. et al. The deubiquitinase USP16 functions as an oncogenic factor in K-RAS-driven lung tumorigenesis. Oncogene 40, 5482–5494 (2021). https://doi.org/10.1038/s41388-021-01964-6

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