The reversible and dynamic O-GlcNAcylation regulates vast networks of highly coordinated cellular and nuclear processes. Despite the dysregulation of the sole enzyme O-GlcNAc transferase (OGT), is showed to associated with the progression of hepatocellular carcinoma (HCC), the mechanisms by which OGT controls the cis-regulatory elements in the genome and achieves transcriptional functions remain unclear. Here, we demonstrate that the elevated OGT increases HCC proliferation and metastasis by orchestrating the transcription of numerous malignant regulators in vitro and in vivo. Diverse transcriptional regulators are recruited by OGT in HCC cells with progressive malignancy, which shapes the genome-wide OGT chromatin cis-elements occupation. Further, an unrecognized cooperation between ZNF263 and OGT is crucial for activating downstream transcriptomics. We reveal that the O-GlcNAcylation site Ser662 is responsible for ZNF263 chromatin association at candidate gene promoters and OGT facilitated HCC the malignant phenotypes. Our data establish the importance of aberrant OGT and ZNF263 O-GlcNAcylation in HCC malignant progression, and represents the pursuit of OGT as a target for HCC therapy. Overall design: We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) using anti-Flag magnetic beads in Flag-OGT stably expressed MHCC-97H and MHCC-97L cells. ZNF263 ChIP-seq was performed using anti-ZNF263 antibody in the above cells. Next, ZNF263 was knockdown by shRNA in 97H/OGT and 97L/OGT cells. HA-ZNF263-WT and HA-ZNF263-S662A ChIP-seq were performed using anti-HA magnetic beads in ZNF263 knockdown cells. Next-generation sequencing libraries were generated and amplified for 15 cycles. 100-300 bp DNA fragments were gel-purified and sequenced with an Illumina NovaSeq 6000 instrument by Novogene Technology (Beijing, China). Two biological replicates of each ChIP-seq were performed. We also analyzed gene expression in Flag-OGT expressed cells by RNA-seq. Antibody used for the study: anti-Flag magnetic beads (Bimake, #B26102), anti-HA-magnetic beads (Bimake, #B26202), anti-ZNF263 antibody (Invitrogen, #PA5-95772, 1:50, added with protein A/G-magnetic beads), anti-H3K27ac antibody (CST, #8173, 1:50, added with protein A/G-magnetic beads), and anti-H3K4me3 antibody (CST, #9751, 1:50, added with protein A/G-magnetic beads) in this study.