EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL

• Published in: Journal of experimental & clinical cancer research 2024-01, Vol.43 (1), p.35-18, Article 35
• Main Authors: Pan, Mingang, Luo, Muyu, Liu, Lele, Chen, Yunmeng, Cheng, Ziyi, Wang, Kai, Huang, Luyi, Tang, Ni, Qiu, Jianguo, Huang, Ailong, Xia, Jie
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - therapy; Cell growth; Cell Line, Tumor; Cell Proliferation; Clinical trials; Cloning; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; EGR1; Gene expression; Gene Expression Regulation, Neoplastic; Gene therapy; Genes; Genetic transcription; Glucose metabolism; Glycolysis; Growth; HCC; Health aspects; Humans; Infectious diseases; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - therapy; Mice; Molecular biology; PFKL; Plasmids; Polymerase chain reaction; Reagents; Sorafenib; Sorafenib - pharmacology; Transcription factors; Tumors
• ISSN: 1756-9966; 0392-9078; 1756-9966
• DOI: 10.1186/s13046-024-02957-5

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. 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. 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. 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.