Sirt1去乙酰化p62/SQSTM1 K295阻滞其泛素化依赖性降解的机制及其在肝癌发生发展中的作用

p62/SQSTM1在肝癌等很多恶性肿瘤中高表达促进肿瘤发生发展，但p62的表达调控机制尚未完全清楚。蛋白乙酰化修饰在调节蛋白表达和功能中起重要作用。我们发现p62可能存在 K295乙酰化，K295乙酰化可促进p62泛素化依赖性降解；肝癌中Sirt1和p62均高表达；抑制Sirt1显著上调p62乙酰化，促进p62泛素化依赖性降解，并抑制细胞增殖，反之亦然；肝细胞Sirt1条件敲除小鼠的肝癌发生明显受抑，且p62表达下调，表明Sirt1可能通过去乙酰化p62 K295阻滞其泛素化依赖性降解，使p62表达上调，促进肝癌发生发展。为证实该假说，我们拟采用一系列分子、细胞和动物实验阐明p62 K295乙酰化动态修饰的调控机制，揭示p62乙酰化促进其泛素化依赖性降解的分子机制，明确Sirt1稳定p62蛋白表达在肝癌中的作用和临床意义，从而为肝癌等p62高表达恶性肿瘤的临床防治提供新的思路和理论依据。

p62/SQSTM1 was aberrantly over-expressed in various cancers such as hepatocellular carcinoma. However, the underlying mechanisms especially autophagy-independent mechanisms for p62 up-regulation in human cancers remain largely undefined. Protein acetylation plays critical role in the regulation of protein expression and function. In our preliminary studies, we found p62 acetylation at K295, and K295 acetylation could promote p62 ubituination dependent degradation. Further screening identified that class III deacetylase Sirt1 might suppress p62 acetylation. Then, we found that both Sirt1 and p62 were highly expressed in hepatocellular carcinoma (HCC). In addition, Sirt1 suppression increased p62 acetylation. Sirt1 knockdown reduced p62 protein expression, increased p62 ubiquitination, inhibited cell growth and vice versa. Furthermore, liver cell conditional Sirt1 knockout remarkably suppressed DEN (Diethylnitrosamine) induced HCC development in mice. Therefore, we proposed that Sirt1 deacetylates p62 to prevent its ubiquitination dependent proteasomal degradation, thus promoting hepatocellular carcinogenesis. To prove this hypothesis, we will perform a series of in vitro and in vivo experiments to investigate the dynamic regulation of p62 K295 acetylation, the mechanism of p62 K295 acetylation in the ubiquitination and proteasomal degradation of p62 in HCC, and the role of Sirt1-p62 axis in hepatocellular carcinogenesis. Taken together, our investigation would provide new insights into autophagy-independent regulation of p62 expression, as well as new evidences for effective cancer therapy based on p62 or Sirt1-targeting strategies.