Sirt1 deacetylates and stabilizes p62 to promote hepato-carcinogenesis |
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| Authors: | Lifeng Feng Miaoqin Chen Yiling Li Muchun Li Shiman Hu Bingluo Zhou Liyuan Zhu Lei Yu Qiyin Zhou Linghui Tan Huimin An Xian Wang Hongchuan Jin |
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| Affiliation: | 1.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 ;2.Department of Pathology, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China ;3.Department of Medical Oncology, Key lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China |
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| Abstract: | 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.Subject terms: Cancer, Post-translational modifications |
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