Liu Zhen, Li Junhe, Ding Yun, Ma Mei, Chen Jun, Lei Wan, Li Li, Yao Yangyang, Yu Xin, Zhong Min, Liao Quan, Fang Weidan, Fan Linwei, Huang Chunye, Zhong Hongguang, Wen Qin, Fang Zi, Chen Jingyi, Huang Shanshan, Xiong Jianpin, Xiang Xiaojun, Deng Jun
Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
Jiangxi Key Laboratory for Individual Cancer Therapy, 17 Yongwai Street, Nanchang, Jiangxi Province, 330006, China.
Oncogene. 2022 Apr;41(18):2555-2570. doi: 10.1038/s41388-022-02267-0. Epub 2022 Mar 22.
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.
河马-Yes相关蛋白1（YAP1）信号通路在胃癌发生和转移中的重要性已引起了相当多的研究关注；然而，YAP1在胃癌（GC）中的调控网络尚未完全明确。在本研究中，泛素特异性蛋白酶49（USP49）被鉴定为YAP1的一种新型去泛素化酶，敲低USP49可抑制GC细胞的增殖、转移、化疗耐药性及腹膜转移。USP49的过表达则显示出相反的生物学效应。此外，USP49由YAP1/TEAD4复合物转录激活，该复合物与YAP1形成正反馈环，促进GC细胞的恶性进展。最后，我们收集了482例GC患者的组织样本和临床随访信息。结果显示，USP49在GC细胞中高表达，且与YAP1及其靶基因结缔组织生长因子（CTGF）和富含半胱氨酸的血管生成诱导因子61（CYR61）的表达呈正相关。生存分析和Cox回归分析表明，USP49高表达与预后不良相关，是一个独立的预后因素。此外，USP49和YAP1高表达的患者总生存期极短。本研究结果表明，USP49/YAP1正反馈环的异常激活在GC的恶性进展中起关键作用，从而为GC提供了潜在的新型预后因素和治疗靶点。
