O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis
O-GlcNAcylation of RACK1 promotes hepatocellular carcinogenesis
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RACK1的O-GlcNAc酰化促进肝细胞癌变
DOI：
10.1016/j.jhep.2018.02.003
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发表时间：
2018-06-01
影响因子：
25.7
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
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作者：
Duan, Fangfang;Wu, Hao;Gu, Jianxin
背景和目标：异常致癌mRNA翻译和蛋白质O-连接的β-N-乙酰葡糖胺化（O-GlcNAc化）是肿瘤发生过程中的一般特征。然而，这两种途径是否以及如何相互联系仍然是未知的。我们的前期研究表明，活化C激酶1的核糖体受体（RACK 1）促进了肝细胞癌（HCC）的耐药和生长。本研究旨在探讨RACK 1的O-GlcNAc化在癌基因翻译和肝癌发生中的作用。以肝癌细胞系为研究对象，研究RACK 1 O-GlcNAc化对癌基因转录和肿瘤细胞体外行为的影响。用转基因敲入小鼠检测RACK 1 O-GlcNAc化在体内调节HCC肿瘤发生中的作用。结果：RACK 1的O-GlcNAc修饰位点位于Ser 122。RACK 1的O-GlcNAc化增强了其蛋白质稳定性、核糖体结合以及与PKC β II（PRKCB）的相互作用，导致HCC细胞中真核翻译起始因子4 E磷酸化和有效癌基因的翻译增加。在体外和二乙基亚硝胺（DEN）诱导的HCC小鼠模型中，RACK 1 O-GlcNAc化Ser 122的基因切除显著抑制肿瘤发生、血管生成和转移。增加RACK 1 O-GlcNAc化也观察到在肝癌患者样本和相关的肿瘤发展和复发后chemotherapy.Conclusions：这些研究结果表明，RACK 1作为关键介质连接O-GlcNAc代谢帽依赖性翻译在肝癌肿瘤发生。RACK 1的O-GlcNAc修饰为肝癌的治疗提供了新的选择。综述：核糖体受体的O-GlcNAc修饰激活了C-激酶1的丝氨酸122位，促进了其稳定性、核糖体定位以及与蛋白激酶PKC β II的相互作用，从而驱动癌基因的翻译和肝癌的发生。激活的C-激酶1的核糖体受体的O-GlcNAc化增加与肝细胞癌患者的肿瘤生长、转移和复发正相关。(C)2018年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Aberrant oncogenic mRNA translation and protein O-linked beta-N-acetylglucosaminylation (O-GlcNAcylation) are general features during tumorigenesis. Nevertheless, whether and how these two pathways are interlinked remain unknown. Our previous study indicated that ribosomal receptor for activated C-kinase 1 (RACK1) promoted chemoresistance and growth in hepatocellular carcinoma (HCC). The aim of this study is to examine the role of RACK1 O-GlcNAcylation in oncogene translation and HCC carcinogenesis.Methods: The site(s) of RACK1 for O-GlcNAcylation was mapped by mass spectrometry analysis. HCC cell lines were employed to examine the effects of RACK1 O-GlcNAcylation on the translation of oncogenic factors and behaviors of tumor cells in vitro. Transgenic knock-in mice were used to detect the role of RACK1 O-GlcNAcylation in modulating HCC tumorigenesis in vivo. The correlation of RACK1 O-GlcNAcylation with tumor progression and relapse were analyzed in clinical HCC samples.Results: We found that ribosomal RACK1 was highly modified by O-GlcNAc at Ser122. O-GlcNAcylation of RACK1 enhanced its protein stability, ribosome binding and interaction with PKC beta II (PRKCB), leading to increased eukaryotic translation initiation factor 4E phosphorylation and translation of potent oncogenes in HCC cells. Genetic ablation of RACK1 O-GlcNAcylation at Ser122 dramatically suppressed tumorigenesis, angiogenesis, and metastasis in vitro and in diethylnitrosamine (DEN)-induced HCC mouse model. Increased RACK1 O-GlcNAcylation was also observed in HCC patient samples and correlated with tumor development and recurrence after chemotherapy.Conclusions: These findings demonstrate that RACK1 acts as key mediator linking O-GlcNAc metabolism to cap-dependent translation during HCC tumorigenesis. Targeting RACK1 O-GlcNAcylation provides promising options for HCC treatment.Lay summary: O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 at the amino acid serine122 promotes its stability, ribosome localization and interaction with the protein kinase, PKC beta II, thus driving the translation of oncogenes and tumorigenesis of hepatocellular carcinoma. Increased O-GlcNAcylation of ribosomal receptor for activated C-kinase 1 is positively correlated with tumor growth, metastasis and recurrence in patients with hepatocellular carcinoma. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.