Department of Clinical Laboratory, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, China.
The Comprehensive Cancer Center and Shanghai Key Laboratory for Pancreatic Diseases, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201620, China.
Cell Signal. 2017 Sep;37:62-73. doi: 10.1016/j.cellsig.2017.06.001. Epub 2017 Jun 2.
Here, bioinformatics data from Sirt1 knock-out (KO) and knock-in (KI) mice suggest that Sirt1 inhibits Wnt/βCatenin signaling in the liver. However, it is unclear how this relationship occurs and how it contributes to malignant phenotypes in liver cancer cells. We found that Sirt1 expression promotes phosphorylation of βCatenin at Ser675, which may subsequently decrease expression of total-βCatenin. Mechanistically, Sirt1 expression elevates phosphorylation of the alpha subunit of protein kinase A (PKAα), and this event is essential for Sirt1-induced phosphorylation of βCatenin. The negative effects of Sirt1 on βCatenin stability are also dependent on PKAα. Stimulating PKAα recruits βTrCP, a well-known ubiquitin E3 ligase for βCatenin, to βCatenin. Interestingly, Sirt1 expression is able to up-regulate βTrCP expression. Finally, we found that malignant phenotypes occur in hepatocytes when Sirt1 and βCatenin are co-overexpressed, and such effects are enhanced by simultaneous knockdown of PKAα. In contrast, malignant phenotypes are abrogated upon knockdown of Sirt1, and this phenotype is magnified by knockdown of βCatenin. Collectively, we conclude that suppression of both Sirt1 and Wnt/βCatenin might be effective in treating liver cancer.
这里，来自 Sirt1 敲除（KO）和敲入（KI）小鼠的生物信息学数据表明，Sirt1 抑制肝脏中的 Wnt/βCatenin 信号通路。然而，目前尚不清楚这种关系是如何发生的，以及它如何导致肝癌细胞中的恶性表型。我们发现 Sirt1 的表达促进了βCatenin 在 Ser675 位的磷酸化，这可能随后降低了总βCatenin 的表达。在机制上，Sirt1 的表达增加了蛋白激酶 A（PKAα）的α亚单位的磷酸化，而这一事件对于 Sirt1 诱导的βCatenin 磷酸化是必不可少的。Sirt1 对βCatenin 稳定性的负向作用也依赖于 PKAα。刺激 PKAα 将βTrCP（βCatenin 的一种著名泛素 E3 连接酶）招募到βCatenin 上。有趣的是，Sirt1 的表达能够上调βTrCP 的表达。最后，我们发现当 Sirt1 和βCatenin 共同过表达时，恶性表型会出现在肝细胞中，并且这种效应会因 PKAα 的同时敲低而增强。相反，当 Sirt1 被敲低时，恶性表型会被消除，而当βCatenin 被敲低时，这种表型会被放大。总之，我们得出结论，抑制 Sirt1 和 Wnt/βCatenin 可能是治疗肝癌的有效方法。
