School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China.
The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
J Cell Physiol. 2021 Nov;236(11):7491-7503. doi: 10.1002/jcp.30385. Epub 2021 Apr 12.
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.
O-糖基化是一种翻译后修饰，可调节许多核内和细胞质蛋白，并且作为各种生物过程（如转录、信号转导和细胞运动）的关键调节剂而出现。尽管越来越多的证据表明，整体 O-糖基化水平的升高与肝癌（HCC）细胞的转移有关，但潜在的机制仍不清楚。在这项研究中，我们证明了叉头框蛋白 A2（FOXA2），一种维持肝脏内稳态和 HCC 发展的必需转录因子，可被 O-糖基转移酶（OGT）O-糖基化，调节 HCC 细胞的迁移和侵袭。FOXA2 和 OGT 在 HCC 组织中的表达趋势相反，FOXA2 水平较低预示着 HCC 患者预后不良。在 HCC 细胞中发现 FOXA2 的减少与细胞 O-糖基化和细胞迁移能力呈负相关。值得注意的是，我们发现 FOXA2 被 O-糖基化修饰，并且 O-糖基化在高度转移性 HCC 细胞中激活了 FOXA2 的泛素化降解。尽管这种修饰不影响 FOXA2 的核定位能力，但 O-糖基化对于减弱 FOXA2 介导的转录至关重要。O-糖基化降低了 FOXA2 下游靶基因 E-钙粘蛋白的转录，最终促进了 O-糖基化介导的 HCC 细胞迁移和侵袭。这些结果深入了解了 O-糖基化在调节 FOXA2 活性中的作用，并提示其在 HCC 转移中的重要意义。
