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Chromatin-associated OGT promotes the malignant progression of hepatocellular carcinoma by activating ZNF263

Oncogene volume 42, pages 2329–2346 (2023)Cite this article

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Abstract

Reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Although dysregulation of the sole enzyme O-GlcNAc transferase (OGT) was shown to be associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and performs transcriptional functions remain unclear. Here, we demonstrate that elevated OGT levels enhance HCC proliferation and metastasis, in vitro and in vivo, by orchestrating the transcription of numerous regulators of malignancy. Diverse transcriptional regulators are recruited by OGT in HCC cells undergoing malignant progression, which shapes genome-wide OGT chromatin cis-element occupation. Furthermore, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcription in HCC cells. We reveal that O-GlcNAcylation of Ser662 is responsible for the chromatin association of ZNF263 at candidate gene promoters and the OGT-facilitated HCC malignant phenotypes. Our data establish the importance of aberrant OGT activity and ZNF263 O-GlcNAcylation in the malignant progression of HCC and support the investigation of OGT as a therapeutic target for HCC.

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Fig. 1: High levels of OGT in HCC are correlated with poor patient prognosis.
Fig. 2: OGT-modulated transcriptomics are responsible for the malignance of HCC in vitro and in vivo.
Fig. 3: Chromatin-associated OGT occupies promoter regions and actives malignant-related genes expression in HCC cells.
Fig. 4: The interactions with ZNF263 shape OGT genomic occupation in HCC cells.
Fig. 5: ZNF263 is O-GlcNAcylated by OGT in HCC cells.
Fig. 6: ZNF263 O-GlcNAcylation governs the expression of downstream metastasis-related genes through modulation of ZNF263 chromatin loci.
Fig. 7: ZNF263 O-GlcNAcylation enhances the metastatic potential of HCC cells.
Fig. 8: ZNF263 O-GlcNAcylation promotes metastasis of HCC cells in vivo.

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Acknowledgements

This study is supported by the National Natural Science Foundation of China (32171282) and the Fundamental Research Funds for the Central Universities (DUT22YG131).

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Author notes

  1. These authors contributed equally: Lingyan Wang, Guofang Li.

Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China

    Lingyan Wang, Guofang Li, Ziyu Zhou, Chang Ge, Yajie Liu, Nana Zhang, Wenli Li, Jianing Zhang & Yubo Liu

  2. Department of Chemistry, The University of Hong Kong, Hong Kong, China

    Qiushi Chen

  3. Laboratory for Synthetic Chemistry and Chemical Biology Limited, Hong Kong, China

    Qiushi Chen

  4. Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, China

    Keren Zhang

  5. Blood Diseases Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Mingshan Niu

  6. Department of Oncology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China

    Xiaomin Zhong

  7. Shenzhen Jingtai Technology Co., Ltd. (XtalPi), Shenzhen, China

    Sijin Wu

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Contributions

YL and JZ conceived and designed the study. LW, GL, ZZ, and CG performed all cell culture experiments and generated samples for LC-MS/MS; QC and KZ performed LC-MS/MS; LW, YL, MN, and XZ provided assistance with animal resources and human samples; LW, YL and NZ acquired images using confocal microscopy; SW performed molecular dynamics simulation; YL and JZ analyzed data; LW, JZ, and YL drafted the manuscript, while all authors provided input into the manuscript.

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Correspondence to Sijin Wu, Jianing Zhang or Yubo Liu.

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Wang, L., Li, G., Zhou, Z. et al. Chromatin-associated OGT promotes the malignant progression of hepatocellular carcinoma by activating ZNF263. Oncogene 42, 2329–2346 (2023). https://doi.org/10.1038/s41388-023-02751-1

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