Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis.
Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis.
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DOI：
10.1038/s41419-021-03666-z
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发表时间：
2021-04-14
影响因子：
9
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Feng L;Chen M;Li Y;Li M;Hu S;Zhou B;Zhu L;Yu L;Zhou Q;Tan L;An H;Wang X;Jin H
p62/SQSTM 1在包括肝细胞癌在内的许多癌症中经常上调。高表达p62通过激活包括Nrf2、mTORC 1和NF κ B信号转导在内的多种信号通路促进肝癌的发生。然而，肝细胞癌中p62上调的潜在机制仍不清楚。在此，我们证实p62在肝细胞癌中上调，其高表达与患者的总生存期较短相关。p62基因在肝癌细胞中的敲低在体外和体内都降低了细胞生长。有趣的是，p62蛋白的稳定性可以通过其在赖氨酸295处的乙酰化来降低，这是由脱乙酰酶Sirt1和乙酰转移酶GCN 5调节的。乙酰化的p62增加了它与E3连接酶Keap1的结合，这促进了它的多聚泛素化依赖性蛋白酶体降解。此外，Sirt1在肝细胞癌中被上调以使p62去乙酰化和稳定。此外，肝细胞Sirt1条件性敲除小鼠在二乙基亚硝胺治疗后发生的肝肿瘤要少得多，这可以通过重新引入外源性p62来逆转。总之，Sirt1使p62在赖氨酸295处脱乙酰化，以干扰Keap1介导的p62多聚泛素化，从而上调p62表达，促进肝癌发生。因此，靶向Sirt1或p62是治疗肝细胞癌的合理策略。
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.
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影响因子：
16
作者：
Pan JA;Sun Y;Jiang YP;Bott AJ;Jaber N;Dou Z;Yang B;Chen JS;Catanzaro JM;Du C;Ding WX;Diaz-Meco MT;Moscat J;Ozato K;Lin RZ;Zong WX
通讯作者：
Zong WX
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
64.5
作者：
Moscat, Jorge;Karin, Michael;Diaz-Meco, Maria T.
通讯作者：
Diaz-Meco, Maria T.
MEK1信号通过维持SIRT1蛋白稳定促进肝癌干细胞的自我更新和致瘤性
影响因子：
--
作者：
Cheng J;Liu C;Liu L;Chen X;Shan J;Shen J;Zhu W;Qian C
通讯作者：
Qian C
影响因子：
21.1
作者：
Song P;Li S;Wu H;Gao R;Rao G;Wang D;Chen Z;Ma B;Wang H;Sui N;Deng H;Zhang Z;Tang T;Tan Z;Han Z;Lu T;Zhu Y;Chen Q
通讯作者：
Chen Q