The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis

Xiao Zhang, Yongxia Qiao, Qi Wu, Yan Chen, Shaowu Zou, Xiangfan Liu, Guoqing Zhu, Yinghui Zhao, Yuxin Chen, Yongchun Yu, Qiuhui Pan, Jiayi Wang () and Fenyong Sun ()
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Xiao Zhang: Shanghai Tenth People’s Hospital of Tongji University
Yongxia Qiao: School of Public Health, Shanghai Jiaotong University School of Medicine
Qi Wu: Shanghai Tenth People’s Hospital of Tongji University
Yan Chen: Shanghai Tenth People’s Hospital of Tongji University
Shaowu Zou: Shanghai Tenth People’s Hospital of Tongji University
Xiangfan Liu: Faculty of Medical Laboratory Science, Shanghai Jiaotong University School of Medicine
Guoqing Zhu: Shanghai Tenth People’s Hospital of Tongji University
Yinghui Zhao: Shanghai Tenth People’s Hospital of Tongji University
Yuxin Chen: Shanghai Tenth People’s Hospital of Tongji University
Yongchun Yu: Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine
Qiuhui Pan: Shanghai Tenth People’s Hospital of Tongji University
Jiayi Wang: Shanghai Tenth People’s Hospital of Tongji University
Fenyong Sun: Shanghai Tenth People’s Hospital of Tongji University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract 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 via in vitro cell-based and in vivo mouse 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.

Date: 2017
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DOI: 10.1038/ncomms15280

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