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USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer

Oncogene volume 41, pages 2555–2570 (2022)Cite this article

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Abstract

The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.

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Fig. 1: Identification of USP49 as an oncogenic USP associated with Hippo-YAP1 in GC.
Fig. 2: USP49 promotes proliferation, metastasis, and drug resistance in GC cells in vitro.
Fig. 3: USP49 directly binds to YAP1 and deubiquitinates and stabilizes it.
Fig. 4: USP49 promotes malignant biological behavior in GC cells through the Hippo-YAP1 pathway.
Fig. 5: USP49 is transcriptionally activated by YAP1/TEAD4.
Fig. 6: USP49 promotes tumor growth and metastasis in vivo.
Fig. 7: USP49 promotes tumor formation in vivo in a YAP1-dependent manner.
Fig. 8: High USP49 expression, in addition to YAP1, is an independent predictor of poor prognosis.

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Acknowledgements

This work was supported by JiangXi Province General Projects (grant 20202BBGL73036), the National Natural Science Foundation of China (grant 81760432), Key Laboratory Fund of Jiangxi Province (grant number: 20202BCD42011), Jiangxi Provincial Outstanding Young Talents projects (grant 2019BCB23020), the Science and Technology Department of Jiangxi Province (grant 20202BBGL73055), Jiangxi Provincial Young Talents projects (grant 20204BCJ23016), the National Natural Science Foundation of China (grant 8216100370), Jiangxi Provincial Outstanding Youth projects (grant 2018ACB21037), the CSCO-Bayer Cancer Research Fund (grant Y-bayer202001/zb-0007), the Science and Technology Department of Jiangxi Province (grant 20202BAB216028), and the Department of Health of Jiangxi Province Projects (grant 2019A058).

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Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China

    Zhen Liu, Junhe Li, Yun Ding, Mei Ma, Jun Chen, Wan Lei, Li Li, Yangyang Yao, Xin Yu, Min Zhong, Quan Liao, Weidan Fang, Linwei Fan, Chunye Huang, Hongguang Zhong, Qin Wen, Zi Fang, Jingyi Chen, Shanshan Huang, Jianpin Xiong, Xiaojun Xiang & Jun Deng

  2. Jiangxi Key Laboratory for Individual Cancer Therapy, 17 Yongwai Street, Nanchang, Jiangxi Province, 330006, China

    Zhen Liu, Yun Ding, Mei Ma, Xin Yu, Min Zhong, Quan Liao, Weidan Fang, Linwei Fan & Zi Fang

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Contributions

JD, JX, and XX designed the study and guided work; ZL, YD, and JL wrote the manuscript; HS, MM, and JC conducted statistics; ZL, CH, and LL made figures; WF, QW, ZL, XY, and QL conducted the cellular and animal experiments; MZ, HZ, ZF, and JC. conducted molecular experiments; YY, LF, and WL collected clinical information. All authors read and approved the final manuscript.

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Correspondence to Shanshan Huang, Jianpin Xiong, Xiaojun Xiang or Jun Deng.

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Liu, Z., Li, J., Ding, Y. et al. USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer. Oncogene 41, 2555–2570 (2022). https://doi.org/10.1038/s41388-022-02267-0

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