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

Lingyan Wang, Guofang Li, Ziyu Zhou, Chang Ge, Qiushi Chen, Yajie Liu, Nana Zhang, Keren Zhang, Mingshan Niu, Wenli Li, Xiaomin Zhong, Sijin Wu*, Jianing Zhang*, Yubo Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)2329-2346
Number of pages18
JournalOncogene
Volume42
Issue number30
DOIs
Publication statusPublished - 21 Jul 2023
Externally publishedYes

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