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首页> 外文期刊>Journal of cellular physiology. >O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity
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O-GlcNAcylation promotes the migratory ability of hepatocellular carcinoma cells via regulating FOXA2 stability and transcriptional activity

机译：O-GlcNAcylation促进迁移的能力通过调节肝细胞癌的细胞FOXA2稳定和转录活动

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摘要

O-GlcNAcylation is a posttranslational modification that regulates numerous nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes, such as transcription, signal transduction, and cell motility. Although increasing evidence has shown that elevated levels of global O-GlcNAcylation are linked to the metastasis in hepatocellular carcinoma (HCC) cells, the underlying mechanism is still ambiguous. In this study, we demonstrated that forkhead box protein A2 (FOXA2), an essential transcription factor for liver homeostasis and HCC developing, was O-GlcNAcylated by O-GlcNAc transferase (OGT) and regulates HCC cells migration and invasion. Opposite FOXA2 and OGT expression tendency were observed in HCC tissues, and lower FOXA2 levels predicted a poor prognosis in HCC patients. The reduction of FOXA2 in HCC cells was found to be inversely correlated with the cellular O-GlcNAcylation and cell migratory ability. Notably, we found that FOXA2 was modified by O-GlcNAcylation and that O-GlcNAcylation activated the ubiquitination degradation of FOXA2 in highly metastatic HCC cells. Although this modification did not affect FOXA2 nuclear localization capability, O-GlcNAcylation on FOXA2 was key for attenuating FOXA2-mediated transcription. O-GlcNAcylation decreased the transcription of FOXA2 downstream target gene E-cadherin and it ultimately promoted O-GlcNAcylation-mediated HCC cell migration and invasion. The results provide insights into the role of O-GlcNAcylation in regulating FOXA2 activity and suggest its important implications in HCC metastasis.
机译：O-GlcNAcylation是转译后的调节众多核和修改胞质蛋白,正成为一个关键等各种生物过程的监管机构转录、信号转导和细胞的能动性。全球O-GlcNAcylation水平升高与肝细胞的转移细胞癌(HCC),底层机制仍然是模棱两可的。证明forkhead盒蛋白A2(FOXA2),一个重要的转录因子肝内稳态和肝癌发展,O-GlcNAcylated O-GlcNAc转移酶(油气痕迹)调节肝细胞迁移和入侵。相反FOXA2和油气痕迹表达趋势肝癌组织中观察到,FOXA2水平较低预测肝癌患者预后不良。减少FOXA2肝癌细胞被发现与细胞负相关O-GlcNAcylation和细胞迁移能力。值得注意的是,我们发现FOXA2被修改O-GlcNAcylation, O-GlcNAcylation激活FOXA2的泛素化降解在高转移性肝癌细胞。修改并不影响FOXA2核本地化能力,O-GlcNAcylation FOXA2关键是衰减FOXA2-mediated吗转录。FOXA2下游靶基因的转录钙粘蛋白,最终提升O-GlcNAcylation-mediated肝癌细胞迁移和入侵。在调节FOXA2 O-GlcNAcylation的角色活动和显示其重要的意义在肝细胞癌转移。

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