Department of General Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
Department of Anesthesiology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
Exp Cell Res. 2021 Aug 1;405(1):112646. doi: 10.1016/j.yexcr.2021.112646. Epub 2021 May 21.
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.
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）中的作用和调控机制尚不清楚。在本研究中，我们表明 USP46 在 HCC 组织中下调，低 USP46 水平与 HCC 患者的预后不良相关。在功能实验中，USP46 的过表达可损害 HCC 细胞的增殖和转移，而 USP46 的敲低则增强了 HCC 细胞在体外和体内的增殖和侵袭能力。此外，我们发现 USP46 通过抑制 YAP1 来抑制 HCC 细胞的增殖和转移。YAP1 的异位表达挽救了 USP46 过表达引起的细胞增殖和转移抑制。在机制上，USP46 通过增加 MST1 的表达促进 YAP1 的降解，而 MST1 蛋白的增加拮抗 YAP1 以抑制 HCC 进展。最后，我们证明 USP46 通过直接结合并减少其泛素化来稳定 MST1 蛋白。总之，我们的研究结果表明，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 激酶活性以抑制肿瘤生长和转移，表明 USP46 的激活可能代表 HCC 的一种潜在治疗策略。
