The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis.
The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis.
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YAP O-GlcNAc 酰化在高糖刺激的肝脏肿瘤发生中的重要作用
DOI：
10.1038/ncomms15280
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发表时间：
2017-05-05
影响因子：
16.6
通讯作者：
Sun F
中科院分区：
文献类型：
--
作者：
Zhang X;Qiao Y;Wu Q;Chen Y;Zou S;Liu X;Zhu G;Zhao Y;Chen Y;Yu Y;Pan Q;Wang J;Sun F
O-GlcNAc化与多种组织来源的肿瘤发生有关，但其在肝脏肿瘤发生中的作用尚不清楚。在这里，我们证明了O-GlcNAc化可以增强Yes相关蛋白（雅普）的表达、稳定性和功能，YAP是Hippo通路的下游转录调节因子，也是肝癌中一种有效的致癌因子。O-GlcNAc化以YAP依赖性方式诱导肝癌细胞的转化表型。在Thr 241处鉴定了雅普的O-GlcNAc位点，并且突变该位点降低了雅普的O-GlcNAc化、稳定性和促肿瘤发生能力，同时增加了雅普磷酸化。更重要的是，我们通过体外细胞实验和小鼠模型实验发现，雅普的O-GlcNAc化是高糖诱导的肝肿瘤发生所必需的。有趣的是，还发现了雅普和整体细胞O-GlcNAc酰化之间的正反馈。我们的结论是，雅普O-GlcNAc酰化是一个潜在的治疗干预点，用于治疗与高血糖水平和可能的糖尿病相关的肝癌。
O-GlcNAcylation has been implicated in the tumorigenesis of various tissue origins, but its function in liver tumorigenesis is not clear. Here, we demonstrate that O-GlcNAcylation can enhance the expression, stability and function of Yes-associated protein (YAP), the downstream transcriptional regulator of the Hippo pathway and a potent oncogenic factor in liver cancer. O-GlcNAcylation induces transformative phenotypes of liver cancer cells in a YAP-dependent manner. An O-GlcNAc site of YAP was identified at Thr241, and mutating this site decreased the O-GlcNAcylation, stability, and pro-tumorigenic capacities of YAP, while increasing YAP phosphorylation. Importantly, we found viain vitrocell-based andin vivomouse model experiments that O-GlcNAcylation of YAP was required for high-glucose-induced liver tumorigenesis. Interestingly, a positive feedback between YAP and global cellular O-GlcNAcylation is also uncovered. We conclude that YAP O-GlcNAcylation is a potential therapeutic intervention point for treating liver cancer associated with high blood glucose levels and possibly diabetes.