E74-like E26 transformation-specific transcription factor 3 in gastric cancer: Functions, mechanisms, and clinical translation - unresolved issues

Table 1 Summary of E74-like E26 transformation-specific transcription factor 3 functions across different tumor types[9-12,19,21,24-28,30-35,37,40-52]

Tumor type	Functional role	Key findings
Gastric cancer[21]	Pro-tumorigenic	ELF3 is significantly overexpressed, an independent risk factor for poor overall survival; directly binds CDH1 promoter to inhibit E-cadherin, inducing EMT; directly binds CXCL11 promoter to inhibit expression, impairing CTL recruitment, mediating immune evasion
Gastric cancer[39]	Potentially tumor-suppressive	FZD5 inhibits ZEB1 expression and prevents EMT through PKC-ELF3 axis; FZD5 and ELF3 associated with longer survival
Gastric cancer[26]	Regulatory relationship	ELF3 directly represses lncRNA UBE2CP3; UBE2CP3 promotes gastric cancer metastasis via miR-138-5p/ITGA2 axis
Gastric cancer[27]	Regulatory relationship	ELF3-AS1 promotes gastric cancer progression by binding hnRNPK and regulating CCL20 expression
Gastric cancer[24,25]	Regulatory relationship	ELF3 mRNA is highly expressed in gastric cancer, correlates with expression of transcription factors such as HNF4A and GATA6
Colorectal cancer[9]	Pro-tumorigenic	Drives β-catenin transactivation, promotes proliferation and invasion; high expression is associated with poor prognosis
Colorectal cancer[41]	Pro-tumorigenic	High mRNA and protein expression associated with increased recurrence rate and shortened relapse-free survival in stage II patients; an independent poor prognostic factor
Colorectal cancer[11]	Therapeutic targeting	In KRAS (G13D)-mutant colorectal cancer, ELF3 core transcription factor of HER2-ELF3-KRAS axis, drives progression and confers cetuximab resistance by upregulating KRAS; small molecule YK1 disrupts ELF3-MED23 interaction, restores drug sensitivity
Hepatocellular carcinoma[10]	Pro-tumorigenic	Increased expression associated with poor prognosis; promotes proliferation, migration, invasion; binds miR-141-3p promoter to inhibit its expression, protecting ZEB1 from silencing and inducing EMT
Non-small cell lung cancer[28]	Pro-tumorigenic	mRNA and protein upregulated, associated with overall survival; ELF3 silencing inhibits proliferation and metastasis; activates PI3K/Akt and ERK pathways
Non-small cell lung cancer[42]	Regulatory relationship	miR-320a-3p directly binds ELF3 mRNA 3'UTR, downregulates ELF3 expression, inhibits proliferation, migration, invasion via PI3K/Akt pathway
Lung adenocarcinoma[37]	Pro-tumorigenic (lineage-specific)	Focal amplification at 1q32.1, gene dosage and promoter hypomethylation affect locus; oncogene in lung adenocarcinoma but not in lung squamous cell carcinoma; required for tumor growth
Endometrial cancer[30]	Pro-tumorigenic	ELF3 knockdown inhibits proliferation and colony formation, promotes E-cadherin expression, inhibits N-cadherin and vimentin, reduces EMT; ELF3 promotes EMT and tumor development by binding TPM1 promoter and inhibiting its transcription
Papillary thyroid cancer[31]	Pro-tumorigenic	Core gene in EMT-related gene expression program GEP3, drives tumor invasion and angiogenesis; ELF3 knockdown inhibits EMT and angiogenesis, reduces cell migration and invasion
Biliary tract cancer[32]	Tumor-suppressive	Directly inhibits ZEB2, upregulates CGN maintaining cell junctions; regulates ALOX5 and CXCL16 affecting immune response; conditioned medium from ELF3-overexpressing cells significantly enhances NK cell and CD8+ T cell migration
Ovarian cancer[33]	Tumor-suppressive	Downregulated expression associated with shortened survival; overexpression inhibits proliferation and anchorage-dependent growth; increases epithelial markers, decreases mesenchymal markers
Ovarian cancer[43]	Pro-tumorigenic (context-specific)	Highly expressed under hypoxic conditions; acts as a transcription factor for IGF1, promotes IGF1 and VEGF secretion, enhances endothelial cell proliferation, migration, and angiogenesis
Bladder urothelial carcinoma[34]	Tumor-suppressive	Downstream component of WNT7B/FZD5 signaling, transcriptionally regulates NOTCH1, exerts tumor-suppressive effects
Bladder cancer[44]	Transcriptional regulator	Single-cell analysis identified anti-apoptotic tumor subpopulation; ELF3 together with CEBPB, EGR1, EZH2 acts as a key transcriptional regulator, interacts with immune and stromal cells via FGF, CXCL, VEGF signaling pathways to promote tumor progression
Bladder cancer[45]	Functional alteration	ELF3 mutation (14%) leads to truncated protein, altering regulatory interactions and upregulating neighboring gene PIK3C2B expression
Breast cancer[35]	Tumor-suppressive	Transcriptional repressor of estrogen receptor α; inhibits receptor dimerization and DNA binding activity by interacting with its DNA-binding domain, suppressing estrogen-dependent cell proliferation
Breast cancer[46]	Pro-tumorigenic	In luminal B and HER2 subtypes, high mRNA expression is associated with worse relapse-free survival; ELF3 knockdown inhibits proliferation, colony formation, and anchorage-independent growth
Breast cancer[47,48]	Upregulated expression	Copy number gain at 1q32 is associated with ELF3 overexpression; among differentially expressed cancer driver genes in triple-negative breast cancer
Pancreatic cancer[49]	Pro-tumorigenic	Negatively regulated by miR-1224-5p; overexpression is associated with poor prognosis and advanced clinical stage; negatively correlated with immune cell infiltration
Pancreatic cancer[50]	Pro-metastatic	Netrin-1-ELF3 positive feedback loop promotes liver metastasis via hepatic stellate cell activation and retinoid signaling
Esophageal squamous cell carcinoma[51]	Downstream target	LINC00886 recruits SIRT7 to reduce H3K18 acetylation level at ELF3 promoter, inhibiting ELF3 expression; ELF3 promotes ZEB1/ZEB2 expression by binding miR-144 promoter, facilitating EMT
Esophageal small cell carcinoma[19]	Increased regulatory activity	ELF3 regulatory activity elevated in extracellular matrix fibroblasts (eCAFs)
Neuroendocrine carcinoma[52]	Pro-tumorigenic	One of super-enhancer-associated transcription factors; ELF3 knockdown leads to reduced cell viability
Prostate cancer[12]	Pro-tumorigenic	Overexpressed in primary and metastatic tumors; induced by IL-1β/NF-κB, interacts with NF-κB subunits p65/p50, enhancing their nuclear translocation and transcriptional activity

EMT: Epithelial-mesenchymal transition; ELF3: E74-like E26 transformation-specific transcription factor 3.

Table 2 Therapeutic agents targeting E74-like E26 transformation-specific transcription factor 3 and related E26 transformation-specific transcription factors

Agent	Target	Mechanism of action	Cancer type	Key finding
YK1 (compound 10)[11,55]	ELF3-MED23 interaction	Disrupts binding interface between ELF3 TAD domain and MED23 (amino acids 391-582), inhibits ELF3-MED23 protein-protein interaction, downregulates HER2 expression	Colorectal cancer (KRAS G13D), gastric cancer (HER2-positive)	Restores cetuximab sensitivity in colorectal cancer, inhibits EMT; significantly reduces HER2 levels and downstream signaling in HER2-positive gastric cancer cells, induces apoptosis and anti-proliferative effects; effective against both trastuzumab-sensitive and -resistant clones
YK-4-279[57-59]	Pan-ETS (EWS-FLI1, ETS1, PAX3-ETS, etc.)	Inhibits ETS factor transcriptional activity, interferes with interaction between ETS family members and PAX3, downregulates MET expression	Ewing sarcoma, melanoma, colon cancer	Inhibits cell growth, invasion, and ETS factor function in melanoma; induces hypersensitivity in p53-deficient BRAF V600E-mutant colon cancer, exerting effects through PARylation-mediated cell death (parthanatos)
(S)-YK-4-279[58]	EWS-FLI1	Optimized enantiomer of YK-4-279 with improved pharmacokinetic properties	Ewing sarcoma	Achieved sustained complete responses in 2 of 6 Ewing sarcoma rat xenograft models based on pharmacokinetic model-guided dosing
BRD32048[62]	ETV1	Directly binds ETV1, modulates ETV1-mediated transcriptional activity, inhibits p300-dependent acetylation, promotes ETV1 degradation	Prostate cancer	Inhibits ETV1-driven cancer cell invasion
EI-4[63]	ETS-1	Inhibits ETS-1 transcription factor activity (specific mechanism may involve inhibiting DNA binding)	Hepatocellular carcinoma	Inhibits hepatocellular carcinoma cell proliferation and invasion

EMT: Epithelial-mesenchymal transition; ETS: E26 transformation-specific; ELF3: E74-like E26 transformation-specific transcription factor 3.