重庆医科大学汪凯的科学博客分享 http://blog.sciencenet.cn/u/Kwang02 重医感染性疾病分子生物学教育部重点实验室——汪凯的学术主页

博文

ONCOGENE: O-GlcNAc糖基化修饰TIP60/KAT5促进肝癌转移的机制

已有 536 次阅读 2021-10-15 08:10 |系统分类:论文交流

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  

KAT5.jpg
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 





http://blog.sciencenet.cn/blog-446272-1308005.html

上一篇:[转载]科兴新冠病毒灭活疫苗第三剂加强免疫提高抗体谱系广度,可交叉中和变异毒株
下一篇:重庆夜跑路线推荐:磁器口-沙滨路—嘉陵江滨江路—渝中区

0

该博文允许注册用户评论 请点击登录 评论 (0 个评论)

数据加载中...

Archiver|手机版|科学网 ( 京ICP备07017567号-12 )

GMT+8, 2021-12-1 06:12

Powered by ScienceNet.cn

Copyright © 2007- 中国科学报社

返回顶部