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O-GlcNAcylation on Rab3A attenuates its effects on mitochondrial oxidative phosphorylation and metastasis in
Weicheng Wu1,2, Xixi Zheng3,4, Jing Wang3,4
1Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Wuweicheng@fudan.edu.cn.
Abstract:
Rab3A is a small Ras-like GTPase critical for membrane traffic. Although the functions of Rab3A have been reported in several cancers, the roles of Rab3A in hepatocellular carcinoma (HCC) have never been determined. To investigate the potential roles of Rab3A in HCC progression, we first determined Rab3A levels in HCC tissues and observed upregulated mRNA and protein levels of Rab3A in most tumor tissues. However, in vitro data showed that decreasing Rab3A in most HCC cell lines conferred no significant effects and overexpressing Rab3A in PLC/PRF/5 cells even inhibited migration and invasion. Meanwhile, the upregulation of Rab3A in HCC patients did not correlate with metastasis or overall survival of HCC patients. These contradict data suggested that Rab3A might act as metastatic suppressor and its effects might be attenuated in most HCC cells. Further experiments revealed that O-GlcNAcylation on Rab3A was key for attenuating Rab3A-mediated effects by regulating its GTP-binding activity, and verified the effects of Rab3A and its aberrant O-GlcNAcylation on HCC metastasis in vitro and in vivo. We also found that Rab3A and its O-GlcNAcylation had opposite roles in mitochondria oxidative phosphorylation (mtOXPHOS), and their functions on HCC metastasis were partially depended on their effects on metabolic reprogramming.
Insights
Rab3A, a GTPase, is upregulated in liver cancer but acts as a suppressor. Its function is attenuated by O-GlcNAcylation, impacting hepatocellular carcinoma metastasis and metabolism.
Area of Science:
- Molecular Biology
- Oncology
- Cell Biology
Background:
- Rab3A is a GTPase involved in membrane trafficking, with known roles in various cancers.
- The specific function of Rab3A in hepatocellular carcinoma (HCC) progression remained undetermined.
- Upregulation of Rab3A mRNA and protein was observed in HCC tissues.
Purpose of the Study:
- To investigate the role of Rab3A in hepatocellular carcinoma (HCC) progression.
- To explore the regulatory mechanisms of Rab3A function in HCC.
- To determine the impact of Rab3A and its modifications on HCC metastasis and metabolism.
Main Methods:
- Quantification of Rab3A mRNA and protein levels in HCC tissues and cell lines.
- In vitro assays to assess the effects of Rab3A modulation on HCC cell migration and invasion.
- In vivo studies to evaluate the role of Rab3A and its O-GlcNAcylation in HCC metastasis.
- Analysis of O-GlcNAcylation status on Rab3A and its impact on GTP-binding activity.
- Assessment of mitochondrial oxidative phosphorylation (mtOXPHOS) and metabolic reprogramming.
Main Results:
- Rab3A was upregulated in most HCC tissues, but its reduction had no significant effect, while overexpression inhibited migration and invasion in some cell lines.
- Rab3A upregulation did not correlate with metastasis or survival in HCC patients, suggesting a potential metastatic suppressor role.
- O-GlcNAcylation of Rab3A was identified as a key mechanism attenuating its effects by regulating GTP-binding activity.
- Aberrant O-GlcNAcylation of Rab3A influenced HCC metastasis in vitro and in vivo.
- Rab3A and its O-GlcNAcylation exhibited opposing roles in mtOXPHOS and partially influenced HCC metastasis via metabolic reprogramming.
Conclusions:
- Rab3A may function as a metastatic suppressor in HCC, with its effects potentially attenuated by O-GlcNAcylation.
- O-GlcNAcylation regulates Rab3A's GTP-binding activity, impacting its role in HCC metastasis.
- The interplay between Rab3A, its O-GlcNAcylation, and metabolic reprogramming influences HCC progression and metastasis.
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