期刊
ONCOGENE
卷 40, 期 50, 页码 6707-6719出版社
SPRINGERNATURE
DOI: 10.1038/s41388-021-02058-z
关键词
-
资金
- National Natural Science Foundation of China [82073251, 82072286, 81872270]
- Natural Science Foundation Project of Chongqing [cstc2018jcyjAX0254, cstc2019jscx-dxwtBX0019, cstc2019jcyj-msxmX0587]
- Talent Development Program of CQMU for Postgraduate [BJRC201913]
- Kuanren talents program of the second affiliated hospital of Chongqing Medical University
- Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-M202000401, KJQN201900429]
- Scientific Research Innovation Project for Postgraduate in Chongqing [CYB21196]
Aberrant glucose metabolism and elevated O-linked beta-N-acetylglucosamine modification are common in hepatocellular carcinoma (HCC), with loss of phosphoenolpyruvate carboxykinase 1 (PCK1) leading to increased protein O-GlcNAcylation and promoting HCC metastasis. Through gain- and loss-of-function studies, it was demonstrated that PCK1 suppresses HCC metastasis by regulating KAT5 O-GlcNAcylation and epigenetically activating TWIST1 and c-Myc to promote epithelial-mesenchymal transition (EMT) in HCC. Targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice, highlighting the link between metabolic enzyme deficiency and epigenetic regulation in HCC metastasis.
Aberrant glucose metabolism and elevated O-linked beta-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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据