EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL
Mingang Pan1, Muyu Luo1, Lele Liu1
1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Chongqing, 400016, China.
Background:
Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. The aim of this study was to identify early growth response 1 (EGR1) as a transcription factor target in HCC and to explore its role and assess the potential of gene therapy utilizing EGR1 for the management of HCC.
Methods:
In this study, both in vitro and in vivo assays were employed to examine the impact of EGR1 on the growth of HCC. The mouse HCC model and human organoid assay were utilized to assess the potential of EGR1 as a gene therapy for HCC. Additionally, the molecular mechanism underlying the regulation of gene expression and the suppression of HCC growth by EGR1 was investigated.
Results:
The results of our investigation revealed a notable decrease in the expression of EGR1 in HCC. The decrease in EGR1 expression promoted the multiplication of HCC cells and the growth of xenografted tumors. On the other hand, the excessive expression of EGR1 hindered the proliferation of HCC cells and repressed the development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse HCC models and in vitro human hepatoma organoid models, thereby providing additional substantiation for the anti-cancer role of EGR1 in HCC. The mechanistic analysis demonstrated that EGR1 interacted with the promoter region of phosphofructokinase-1, liver type (PFKL), leading to the repression of PFKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the sensitivity of HCC cells and xenografted tumors to sorafenib was found to be increased by EGR1.
Conclusion:
Our findings suggest that EGR1 possesses therapeutic potential as a tumor suppressor gene in HCC, and that EGR1 gene therapy may offer benefits for HCC patients.
Insights
Early Growth Response 1 (EGR1) acts as a tumor suppressor in Hepatocellular Carcinoma (HCC). EGR1 gene therapy shows promise for managing HCC by inhibiting cancer cell growth and enhancing drug sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Hepatocellular Carcinoma (HCC) presents a significant global health challenge with limited therapeutic options.
- Identifying novel therapeutic targets is crucial for improving HCC treatment outcomes.
Purpose of the Study:
- To identify early growth response 1 (EGR1) as a transcription factor target in HCC.
- To explore the role of EGR1 in HCC progression and its potential for gene therapy.
Main Methods:
- In vitro and in vivo assays were used to assess EGR1's impact on HCC growth.
- Mouse HCC models and human organoid assays evaluated EGR1 gene therapy efficacy.
- Molecular mechanisms of EGR1-mediated gene regulation and HCC suppression were investigated.
Main Results:
- Reduced EGR1 expression correlated with increased HCC cell proliferation and tumor growth.
- EGR1 overexpression inhibited HCC cell proliferation and tumor development.
- EGR1 gene therapy demonstrated efficacy in preclinical models.
- EGR1 repressed PFKL gene expression, inhibiting aerobic glycolysis.
- EGR1 enhanced HCC sensitivity to sorafenib.
Conclusions:
- EGR1 functions as a tumor suppressor gene in HCC.
- EGR1 gene therapy holds therapeutic potential for HCC patients.
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