O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis

摘要：

Aberrant glucose metabolism and elevated O-linked β-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.

关键词：蛋白质翻译后修饰；氧连接N-乙酰葡萄糖胺修饰，O-GlcNAc糖基化修饰；肝癌；肺转移；磷酸烯醇式丙酮酸羧激酶1；糖异生作用；肿瘤代谢。

Liu, R.（刘芮）, Gou, D.（苟冬梅）, Xiang, J.（向进） et al. O-GlcNAc modified-TIP60/KAT5 is required for PCK1 deficiency-induced HCC metastasis. Oncogene (2021). https://doi.org/10.1038/s41388-021-02058-z  

Schematic working model of PCK1 deficiency-mediated HCC metastasis.Gluconeogenesis enzyme PCK1 depletion promotes OGT-mediated O-GlcNAcylation of KAT5, thereby inhibiting its ubiquitination and degradation. Stabilized KAT5 promotes HCC metastasis through inducing the expression of EMT-related genes. DON 6-diazo-5-oxo-L-norleucine.

 原文链接： https://www.nature.com/articles/s41388-021-02058-z