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OGT regulated O-GlcNAcylation promotes papillary thyroid cancer malignancy via activating YAP

Oncogene volume 40, pages 4859–4871 (2021)Cite this article

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Abstract

The incidence of thyroid cancer is growing rapidly during the past decades worldwide. Although most thyroid tumors are curable, some patients diagnosed with distant metastases are associated with poor prognosis. The molecular mechanisms underlying these cases are still largely unknown. Here we found that the upregulated O-Linked N-Acetylglucosamine Transferase (OGT) expression and O-GlcNAcylation (O-GlcNAc) modification in papillary thyroid cancer (PTC) were essential in tumor growth and metastasis. Mass spectrometry analysis showed that YAP was the effector protein modified by OGT. In details, YAP Ser109 O-GlcNAcylation promoted the malignant phenotypes in PTC cells by inducing YAP Ser127 dephosphorylation and activation. Our work clearly showed the critical role of OGT and YAP played in PTC tumors and made it possible for us to seek the clinical potential of manipulating OGT/YAP activity in PTC targeted therapies. These findings also confirmed OGT worked in collaboration with classical Hippo pathway kinases as an upstream regulator of YAP in PTC tumors.

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Fig. 1: Upregulation of O-GlcNAcylation is associated with clinicopathological features in papillary thyroid cancer tissues.
Fig. 2: OGT dysregulations modulate PTC cell proliferation, migration, and invasion.
Fig. 3: OGT stably interacts with and O-GlcNAcylates YAP.
Fig. 4: O-GlcNAcylation regulates YAP translocation and stability via phosphorylation.
Fig. 5: YAP O-GlcNAcylation mainly occurs at Serine109 site.
Fig. 6: O-GlcNAcylation-mediated PTC cell malignancy is dependent on YAP.
Fig. 7: OGT promotes PTC malignancy via YAP in vivo.
Fig. 8: Schematic model showing that O-GlcNAc/YAP signaling promotes tumor malignancy in PTC.

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Acknowledgements

This work was supported by grant no. 81602326 from the National Nature Science Foundation of China and Science and Technology Commission of Shanghai Municipality (No. 15411952503).

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  1. These authors contributed equally: Xiaoyan Li, Zhengming Wu.

Authors and Affiliations

  1. Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Xiaoyan Li, Jing He, Yiting Jin, Chengyu Chu, Yun Cao, Fei Gu, Hongying Wang & Qiang Zou

  2. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA

    Zhengming Wu

  3. Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Chenjian Hou & Xiuping Liu

  4. Department of Pathology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China

    Xiuping Liu

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Contributions

XYL, ZMW, XPL, and QZ designed the study. XYL and ZMW performed the experiments and drafted the manuscript. JH, YTJ, and HYW analyzed the data. CYC, YC and FG collected clinical samples and patients’ information. CJH and XPL evaluated the histological features. XPL and QZ supervised the study and critically revised the manuscript. All authors have reviewed and approved the paper.

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Correspondence to Xiuping Liu or Qiang Zou.

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Li, X., Wu, Z., He, J. et al. OGT regulated O-GlcNAcylation promotes papillary thyroid cancer malignancy via activating YAP. Oncogene 40, 4859–4871 (2021). https://doi.org/10.1038/s41388-021-01901-7

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