A20 interacts with mTORC2 to inhibit the mTORC2/Akt/Rac1 signaling axis in hepatocellular carcinoma cells
A20 interacts with mTORC2 to inhibit the mTORC2/Akt/Rac1 signaling axis in hepatocellular carcinoma cells
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DOI：
10.1038/s41417-022-00562-2
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发表时间：
2022-11
影响因子：
6.4
通讯作者：
Xinyu Wang;Ying Xiao;Yanlei Dong;Zhida Wang;Jing Yi;Jianing Wang;Xiaoyan Wang;Huai-yu Zhou;Lining Zhang;Yongyu Shi
中科院分区：
文献类型：
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作者：
Xinyu Wang;Ying Xiao;Yanlei Dong;Zhida Wang;Jing Yi;Jianing Wang;Xiaoyan Wang;Huai-yu Zhou;Lining Zhang;Yongyu Shi
A20在肝细胞癌中起抑瘤作用，尤其能抑制恶性细胞的转移。然而，A20发挥抑制作用的机制尚不完全清楚。Rac1信号在肝细胞癌转移过程中对细胞迁移至关重要。然而，A20是否以及如何抑制Rac1信号通路抑制肝癌细胞的迁移尚不清楚。因此，我们通过功能增益和损失实验分析了A20与Rac1激活之间的关系，以及Rac1上游两个信号成分Akt和mTORC2的活性。我们发现，过表达A20抑制肝癌细胞中Rac1、Akt和mTORC2的激活，而敲低或敲除A20则促进其激活。此外，A20对mTORC2/Akt/Rac1信号轴的抑制作用是由于A20与mTORC2复合物之间的相互作用。A20与mTORC2的结合是由mTORC2复合体中A20和M1泛素链的ZnF7结构域介导的。此外，在肝癌异种移植小鼠模型中，A20通过抑制mTORC2抑制肝癌细胞的转移。这些发现揭示了A20与mTORC2之间的关系，并解释了A20抑制肝癌转移的分子机制。
A20 acts as a tumor suppressor in hepatocellular carcinoma, especially inhibiting metastasis of the malignant cells. However, the mechanisms whereby A20 plays the inhibitory roles are not understood completely. Rac1 signaling is essential for cell migration in hepatocellular carcinoma metastasis. Nevertheless, it is not known whether and how A20 inhibits Rac1 signaling to suppress the migration of hepatocellular carcinoma cell. Thereby, we analyzed the relationship between A20 and Rac1 activation, as well as the activity of Akt and mTORC2, two signaling components upstream of Rac1, using gain and loss of function experiments. We found that the overexpression of A20 repressed, while the knockdown or knockout of A20 promoted, the activation of Rac1, Akt and mTORC2 in hepatocellular carcinoma cells. Moreover, the inhibitory effect of A20 on the mTORC2/Akt/Rac1 signaling axis was due to the interaction between A20 and mTORC2 complex. The binding of A20 to mTORC2 was mediated by the ZnF7 domain of A20 and M1 ubiquitin chain in the mTORC2 complex. Furthermore, A20 inhibited metastasis of hepatocellular carcinoma cells via restraining mTORC2 in a hepatocellular carcinoma xenograft mouse model. These findings revealed the relationship between A20 and mTORC2, and explained the molecular mechanisms of A20 in inhibition of hepatocellular carcinoma metastasis.