Key Takeaways & Executive Findings
- •• ELF3 is overexpressed in LUAD tissues and correlates with poor prognosis. • ELF3 promotes LUAD cell proliferation, migration, invasion, and glycolysis via transcriptional regulation of HK2 and GLUT1. • USP18 deubiquitinates and stabilizes ELF3, enhancing its oncogenic effects. • Dacinostat, a small-molecule inhibitor targeting ELF3, suppresses LUAD malignant progression.
Abstract
E74-like ETS transcription factor 3 (ELF3) has been implicated in various tumorigenesis and inflammatory diseases. However, its expression profile and role in lung adenocarcinoma (LUAD) remain poorly defined. In the present study, through comprehensive clinical and experimental analyses, we aim to clarify the association between ELF3 overexpression in LUAD tissues and poor prognosis. Functional assays reveal that ELF3 knockdown inhibits the proliferation, migration, and invasion of LUAD cells, while ELF3 overexpression enhances these functions. Pathway enrichment analysis indicates that ELF3 influences the metabolic processes of LUAD. Mechanistically, ELF3 exerts oncogenic effects by regulating the transcription of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1). High-throughput screening reveals that dacinostat, by targeting the active site of the ELF3 protein, attenuates the glycolytic, proliferative, and metastatic abilities of LUAD cells. Additionally, ubiquitin-specific peptidase 18 (USP18) strengthens the stability of the ELF3 protein and influences the malignant biological behavior of LUAD through ELF3. In conclusion, the USP18/ELF3/HK2 and USP18/ELF3/GLUT1 axes play critical roles in glucose metabolism, proliferation, and metastasis of LUAD cells. Dacinostat inhibits the malignant progression of LUAD by targeting ELF3, providing strong evidence for developing novel therapeutic strategies targeting ELF3.
1. Introduction
Globally, lung cancer represents the foremost source of cancer-induced mortality, constituting nearly 18% of all cancer fatalities [1], with lung adenocarcinoma (LUAD) being the typical histological subtype [2]. In the context of using existing therapeutic approaches, there are usually poor curative effects for lung cancer, particularly in advanced stages, due to the tumors’ robust proliferative capabilities and inherent drug resistance [1]. Consequently, there is an urgent need to screen highly specific and sensitive biomarkers for enhancing diagnostic precision and improving the prognosis of LUAD patients.
E-twenty-six (ETS) family member E74-like ETS transcription factor 3 (ELF3) [3,4] is implicated in numerous biological processes and human diseases, encompassing various inflammatory conditions, immune-related disorders, and tumors [5,6]. Its functional role and expression profile appear to differ across malignancies. It may facilitate the progression of prostate cancer [7], hepatocellular carcinoma [8], and cervical cancer [9]. Conversely, reduced ELF3 expression was observed in bladder cancer [10] and biliary tract cancers [11], which appears to inhibit tumor advancement. Despite the considerable body of literature addressing ELF3 in the context of tumors, its specific role in LUAD and the underlying molecular mechanisms remain to be fully elucidated.
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ZENG Yu, YI Yeran, ZHANG Qinfen, LI Li, ZHAO Xiaohe, JIN Haixia, HUANG Ziqi, GUO Shiwei, WANG Qiyu, SHEN Meng, LI Baihui, YANG Lili, ZHAO Weipeng (2026). USP18-stabilized ELF3 drives glycolysis and malignant progression in lung adenocarcinoma. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2026082
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Frequently Asked Questions
What is the role of ELF3 in lung adenocarcinoma?
ELF3 is overexpressed in LUAD tissues and promotes tumor progression by enhancing proliferation, migration, invasion, and glycolysis. It transcriptionally upregulates HK2 and GLUT1, key glycolytic genes.
How does USP18 affect ELF3 in LUAD?
USP18 deubiquitinates ELF3, thereby increasing its protein stability and enhancing its oncogenic functions in LUAD cells.
What is the mechanism of dacinostat in LUAD?
Dacinostat targets the active site of ELF3 protein, inhibiting its activity and thereby attenuating glycolysis, proliferation, and metastasis of LUAD cells.
What are the downstream targets of ELF3 in LUAD?
ELF3 regulates the transcription of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1), which are critical for glycolysis and malignant progression.
What is the clinical significance of ELF3 expression in LUAD?
High ELF3 expression is associated with poor prognosis in LUAD patients, suggesting its potential as a prognostic biomarker and therapeutic target.
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