Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang Province, Cancer Institute of Zhejiang University, Sir Run Run Shaw hospital, School of Medicine, Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
Department of Pathology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Cell Death Dis. 2021 Apr 14;12(4):405. doi: 10.1038/s41419-021-03666-z.
p62/SQSTM1 is frequently up-regulated in many cancers including hepatocellular carcinoma. Highly expressed p62 promotes hepato-carcinogenesis by activating many signaling pathways including Nrf2, mTORC1, and NFκB signaling. However, the underlying mechanism for p62 up-regulation in hepatocellular carcinoma remains largely unclear. Herein, we confirmed that p62 was up-regulated in hepatocellular carcinoma and its higher expression was associated with shorter overall survival in patients. The knockdown of p62 in hepatocellular carcinoma cells decreased cell growth in vitro and in vivo. Intriguingly, p62 protein stability could be reduced by its acetylation at lysine 295, which was regulated by deacetylase Sirt1 and acetyltransferase GCN5. Acetylated p62 increased its association with the E3 ligase Keap1, which facilitated its poly-ubiquitination-dependent proteasomal degradation. Moreover, Sirt1 was up-regulated to deacetylate and stabilize p62 in hepatocellular carcinoma. Additionally, Hepatocyte Sirt1 conditional knockout mice developed much fewer liver tumors after Diethynitrosamine treatment, which could be reversed by the re-introduction of exogenous p62. Taken together, Sirt1 deacetylates p62 at lysine 295 to disturb Keap1-mediated p62 poly-ubiquitination, thus up-regulating p62 expression to promote hepato-carcinogenesis. Therefore, targeting Sirt1 or p62 is a reasonable strategy for the treatment of hepatocellular carcinoma.
p62/SQSTM1 在包括肝细胞癌在内的许多癌症中经常上调。高表达的 p62 通过激活包括 Nrf2、mTORC1 和 NFκB 信号在内的许多信号通路促进肝癌发生。然而，p62 在肝细胞癌中上调的潜在机制在很大程度上仍不清楚。在此，我们证实 p62 在肝细胞癌中上调，其高表达与患者总生存期缩短相关。在肝细胞癌细胞中敲低 p62 可降低体外和体内的细胞生长。有趣的是，p62 蛋白稳定性可通过赖氨酸 295 的乙酰化降低，该过程由去乙酰化酶 Sirt1 和乙酰转移酶 GCN5 调节。乙酰化的 p62 增加了与 E3 连接酶 Keap1 的结合，从而促进其多泛素化依赖的蛋白酶体降解。此外，Sirt1 在肝细胞癌中上调以去乙酰化和稳定 p62。此外，经二乙基亚硝胺处理后，肝细胞 Sirt1 条件性敲除小鼠肝脏肿瘤的形成明显减少，而外源性 p62 的重新引入可逆转这一现象。综上所述，Sirt1 在赖氨酸 295 处去乙酰化 p62，扰乱 Keap1 介导的 p62 多泛素化，从而上调 p62 表达以促进肝癌发生。因此，靶向 Sirt1 或 p62 是治疗肝细胞癌的一种合理策略。
