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

Author

Listed:
  • 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
    Present address: Department of Laboratory Medicine, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China)

  • Jiayi Wang

    (Shanghai Tenth People’s Hospital of Tongji University)

  • Fenyong Sun

    (Shanghai Tenth People’s Hospital of Tongji University)

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.

Suggested Citation

  • Xiao Zhang & Yongxia Qiao & Qi Wu & Yan Chen & Shaowu Zou & Xiangfan Liu & Guoqing Zhu & Yinghui Zhao & Yuxin Chen & Yongchun Yu & Qiuhui Pan & Jiayi Wang & Fenyong Sun, 2017. "The essential role of YAP O-GlcNAcylation in high-glucose-stimulated liver tumorigenesis," Nature Communications, Nature, vol. 8(1), pages 1-15, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15280
    DOI: 10.1038/ncomms15280
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    Cited by:

    1. Yi Lei & Qiangyun Liu & Binggui Chen & Fangfang Wu & Yiming Li & Xue Dong & Nina Ma & Ziru Wu & Yanfang Zhu & Lu Wang & Yuxin Fu & Yuming Liu & Yinting Song & Mei Du & Heng Zhang & Jidong Zhu & Timoth, 2024. "Protein O-GlcNAcylation coupled to Hippo signaling drives vascular dysfunction in diabetic retinopathy," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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