Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1
Deubiquitinating enzyme USP46 suppresses the progression of hepatocellular carcinoma by stabilizing MST1
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DOI：
10.1016/j.yexcr.2021.112646
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发表时间：
2021-06-11
影响因子：
3.7
通讯作者：
Yan, Jinlong
中科院分区：
文献类型：
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作者：
Qiu, Yumin;Huang, Dan;Yan, Jinlong
去泛素化酶 USP46（泛素特异性蛋白酶 46）与多种癌症有关。然而，其在HCC（肝细胞癌）中的作用和调节机制仍不清楚。在这项研究中，我们发现 USP46 在 HCC 组织中下调，并且 USP46 水平低与 HCC 患者预后不良相关。在功能实验中，USP46的过度表达会损害HCC细胞的增殖和转移，而USP46的敲低则增强了体外和体内细胞的增殖和侵袭性。此外，我们发现USP46通过抑制YAP1来抑制HCC细胞增殖和转移。 YAP1的异位表达挽救了USP46过表达引起的细胞增殖和转移的抑制。从机制上讲，USP46通过增加MST1的表达来促进YAP1的降解，而MST1蛋白的增加会拮抗YAP1从而抑制HCC进展。最后，我们证明 USP46 通过直接结合 MST1 蛋白并减少其泛素化来稳定 MST1 蛋白。综上所述，我们的结果表明 USP46 可能是 HCC 中的一种新型肿瘤抑制因子。此外，USP46 作为 MST1 的去泛素化酶，增强 MST1 激酶活性，从而抑制肿瘤生长和转移，表明 USP46 激活可能代表 HCC 的潜在治疗策略。
The deubiquitinating enzyme USP46 (ubiquitin-specific protease 46) is implicated in various cancers. However, its role and regulatory mechanism in HCC (hepatocellular carcinoma) are still unknown. In this study, we showed that USP46 is downregulated in HCC tissues and that low USP46 levels are associated with poor prognosis in HCC patients. In functional experiments, overexpression of USP46 impaired proliferation and metastasis of HCC cells, whereas knockdown of USP46 enhanced cell proliferation and invasiveness in vitro and in vivo. Furthermore, we found that USP46 suppresses HCC cell proliferation and metastasis by inhibiting YAP1. Ectopic expression of YAP1 rescued the inhibition of cell proliferation and metastasis caused by USP46 overexpression. Mechanistically, USP46 promotes the degradation of YAP1 by increasing expression of MST1, and the increase in MST1 protein antagonizes YAP1 to suppress HCC progression. Finally, we demonstrated that USP46 stabilizes the MST1 protein by directly binding to it and decreasing its ubiquitination. Taken together, our results demonstrated that USP46 may be a novel tumor suppressor in HCC. Moreover, USP46 acts as a deubiquitinating enzyme of MST1 to potentiate MST1 kinase activity to suppress tumor growth and metastasis, indicating that USP46 activation may represent a potential treatment strategy for HCC.