O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis.
Aberrant glucose metabolism and elevated O-linked ?-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper ... O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
Mesh Terms:
Acetylation, Acetylglucosamine, Animals, Apoptosis, Carcinoma, Hepatocellular, Cell Proliferation, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Liver Neoplasms, Lung Neoplasms, Lysine Acetyltransferase 5, Mice, Mice, Inbred BALB C, Mice, Nude, Phosphoenolpyruvate Carboxykinase (GTP), Protein Processing, Post-Translational, Trans-Activators, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Acetylation, Acetylglucosamine, Animals, Apoptosis, Carcinoma, Hepatocellular, Cell Proliferation, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Liver Neoplasms, Lung Neoplasms, Lysine Acetyltransferase 5, Mice, Mice, Inbred BALB C, Mice, Nude, Phosphoenolpyruvate Carboxykinase (GTP), Protein Processing, Post-Translational, Trans-Activators, Tumor Cells, Cultured, Ubiquitination, Xenograft Model Antitumor Assays
Oncogene
Date: Dec. 01, 2020
PubMed ID: 34650217
View in: Pubmed Google Scholar
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