Identification of EGR4 as a prospective target for inhibiting tumor cell proliferation and a novel biomarker in colorectal cancer

• Published in: Cancer gene therapy 2024-06, Vol.31 (6), p.871-883
• Main Authors: Wang, Bangting, Zhang, Shijie, Wang, Haiyang, Wang, Min, Tao, Yuwen, Ye, Mujie, Fan, Zhining, Wang, Yan, Liu, Li
• Format: Article
• Language: English
• Subjects: 13/1; 13/105; 13/89; 38/91; 45/77; 5-Fluorouracil; 631/208/68; 631/67/1504; Animals; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer therapies; Cell growth; Cell Line, Tumor; Cell Proliferation; Chromatin remodeling; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm; EGR-4 protein; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Therapy; Humans; Male; Mice; Microenvironments; NF-κB protein; Nuclear transport; Oxaliplatin; Oxaliplatin - pharmacology; Oxaliplatin - therapeutic use; Pathogenesis; Prognosis; Prospective Studies; Signal transduction; Therapeutic targets; Tumorigenesis
• ISSN: 0929-1903; 1476-5500; 1476-5500
• DOI: 10.1038/s41417-024-00743-1

EGR4 (Early Growth Response 4) is a member of the EGR family, involving in tumorigenesis. However, the function and action mechanism of EGR4 in the pathogenesis of colorectal cancer (CRC) remain unclear. To address this, we assessed the prognosis of CRC based on EGR4 using the Kaplan-Meier plotter tool and tissue microarray. The abundance of immunoinfiltration was evaluated through ssGSEA, TISIDB, and TIMER. In vitro experiments involving knockdown or overexpression of EGR4 were performed, and RNA-sequencing was conducted to explore potential mechanisms. Furthermore, we used oxaliplatin and 5-fluorouracil to validate the impact of EGR4 on chemo-resistance. Pan-cancer analysis and tissue microarray showed that EGR4 was highly expressed in CRC and significantly correlated with an unfavorable prognosis. Moreover, EGR4 expression was associated with immunoinfiltration and cancer-associated fibroblasts in the CRC microenvironment. Functional enrichment demonstrated that high-expressional EGR4 were involved in chromatin and nucleosome assembly. Additionally, EGR4 promoted the proliferation of CRC cells. Mechanistically, EGR4 upregulated TNFα to activate the NF-κB signaling pathway, and its knockdown reduced p65 nuclear translocation. Importantly, combining shEGR4 with oxaliplatin and 5-fluorouracil significantly inhibited CRC proliferation. Taken together, these findings provide new insights into the potential prognosis and therapeutic targets of EGR4 in CRC.