Transcriptional regulation modulates gene expression through tightly coordinated temporal and spatial interactions between transcription machinery (including RNA polymerase II, trans-acting factors and associated cofactors) and regulatory elements on chromosomal DNA (1,41). During the initiation phase of gene transcription, general transcription factors associate with the promoter region of the gene and bind to RNA polymerase II; however, efficient transcription is difficult at this stage (1,2). Transcription factors, also known as trans-acting factors, are proteins that directly or indirectly recognize and bind to core sequences of specific cis-acting elements. With the assistance of gene-specific transcription factors, they can induce RNA polymerase II to form an effective transcription initiation complex, thereby exerting efficient transcriptional regulation (1). Thus, the variation in gene expression leading to different types of cellular differentiation (such as morphological features, biological functions and proliferative capacity) is largely regulated by transcription factors. For example, Tsoyi et al (42) demonstrated that the transcription factor specificity protein 1 binds to the ELK3 promoter to promote its expression. Zinc finger E-box binding homeobox 1 (ZEB1), a zinc finger transcription factor, not only recruits co-repressors or co-activators, but also binds to specific DNA sequences containing E-box elements to regulate target gene expression. In studies of breast and pancreatic cancer, ZEB1 has been shown to directly bind to ELK3 target genes to enhance their expression (14,43). Research by Park and Park (44) revealed that the ELK3 promoter region contains a transcription factor SMAD3 binding site, which can directly activate transcription and increase expression.

Post-transcriptional regulation of gene expression serves a crucial role in various cellular processes, including cell development, metabolism and cancer progression. Immediately after transcription initiates the formation of mRNA precursors, these precursors are enveloped by numerous proteins forming ribonucleoprotein complexes. mRNA-binding proteins associate with nascent mRNA precursors and mediate various RNA processing reactions, ultimately yielding mature mRNA (45). N6-Methyladenine is the most common post-transcriptional modification in eukaryotic mRNA. Methylation modifications in the 5′UTR region of mRNA serve crucial roles in mRNA splicing, editing, stability, degradation and polyadenylation, while methylation in the 3′UTR region facilitates nuclear export, translation initiation and maintains mRNA structural stability in conjunction with polyA-binding proteins (46). Methyltransferase-like protein 11A (METTL11A) binds to the 5′UTR region for methylation. Zhang et al (34) demonstrated that METTL11A can promote tumor progression by upregulating ELK3 in cervical cancer. MicroRNAs (miRNAs/miRs) are a class of regulatory, endogenously expressed non-coding small RNA molecules that primarily control mRNA expression by binding to the 3′UTR (47). Studies have indicated that miR-507, miR-200a, miR-3612, miR-155-5p, miR-890 and miR-135a suppress ELK3 expression (45,48–52). Based on the mechanism of miRNA-mediated gene suppression, long non-coding RNAs can exert competing endogenous RNA (ceRNA) regulatory functions by competitively binding to shared miRNA sequences and affecting the expression levels of their downstream target mRNA (53). Xia et al (52) demonstrated that Linc00662/miR-890 regulates ELK3 expression in melanoma via a ceRNA mechanism. Similarly, Linc00525/miR-507 and Linc01106/miR-3612 regulate ELK3 in colorectal cancer and bladder cancer, respectively.

PTM of proteins refers to covalent and generally enzyme-catalyzed modifications occurring after protein biosynthesis. After mRNA is translated into polypeptide chains, PTMs occur to form mature protein products; this process forms the molecular basis for protein dynamic equilibrium and interactions, participating in nearly all biological processes (54). Among PTMs, we have previously demonstrated that acetylation modifies ELK3 to inhibit its transcriptional activity, whereas phosphorylation by Ras promotes its transcriptional activity. Furthermore, Yoo et al (55) investigated a novel mechanism of ELK3 phosphorylation in breast cancer, revealing that ELK3 serves as a substrate for ribosomal S6 kinase 2, which phosphorylates ELK3 to mediate its activation. Gross et al (56) also demonstrated that ELK3 ubiquitination levels are increased under hypoxic conditions, leading to reduced ELK3 expression (Fig. 4).

Tumor cells exhibit 10 hallmark characteristics, among which the maintenance of chronic proliferation is the most fundamental feature (57). Normal cells are regulated by multiple signals that promote or inhibit proliferation, guiding cells into normal division and growth cycles. This ensures proper cell numbers and morphology, thereby maintaining normal tissue structure and function. By contrast, tumor cells can operate independently of these regulatory signals, acquiring the ability for unlimited proliferation. Research has indicated that ELK3 promotes cell proliferation in multiple tumor types, including glioma, pancreatic cancer, breast cancer and melanoma (12–15,58). Park et al (59) demonstrated that ELK3 can promote the tumor-associated lymphatic secretion of exosomes. Exosomes enriched with ELK3 increase the expression of oncogenic miR-30e-3p in tumor cells, while downregulating the expression of tumor-suppressing miR-503-3p and miR-4269, thereby driving breast cancer proliferation (15). ELK3 also regulates the cell cycle, where checkpoints serve as critical control points for proliferation. The G₁-S checkpoint governs cell entry into S phase, the S checkpoint prevents DNA-damaged cells from synthesizing DNA, and the G₂ checkpoint blocks damaged cells from entering mitosis (60). Mao et al (16) demonstrated that ELK3 downregulation in prostate cancer cells increased S-phase and G₂-M phase durations by 58 and 62%, respectively, thus promoting tumor proliferation. Activated ELK3 can also bind to SRF and associate with the SRE of the c-fos proto-oncogene, promoting its oncogenic activity (3,21,55). A study on pancreatic cancer demonstrated that ELK3 overexpression suppresses c-fos transcription via its dual inhibitory domains NID and CID, thereby downregulating c-fos expression and restraining the proliferation of pancreatic cancer cells (61). Whether ELK3 facilitates cell proliferation in pancreatic cancer remains controversial; however, most existing studies generally regard ELK3 as an oncogene that accelerates the proliferation of solid tumors, marking it as a promising biomarker.

Metastasis represents another critical tumor characteristic, and a primary cause of treatment resistance and mortality. Tumor cell dissemination primarily occurs via two pathways: Lymphatic invasion, where cells infiltrate lymph nodes and drain to distant organs; and hematogenous spread, where cells circulate through the bloodstream to distant sites such as the liver, brain, bone or lungs. Abnormal expression of genes associated with tumor metastasis often enhances metastatic potential. Studies have confirmed that ELK3 influences cell metastasis in multiple tumor types (12,14,16–20,62,63). For example, Sloan et al (17) demonstrated that ELK3 may affect caveolin-1 transcription in lung cancer, thereby altering cancer cell metastatic capacity. Choi et al (64) demonstrated that ELK3 regulates ID4 promoter activity, and the ELK3-ID4 axis modulates metastatic properties in triple-negative breast cancer cells. Additionally, it has been indicated that ELK3 promotes ovarian cancer cell migration and invasion by targeting AEG1 (65).

Moreover, inhibiting tumor metastasis is notably more challenging than suppressing tumor cell proliferation, as metastasis involves a number of complex interactions between tumors and the extracellular matrix (ECM). The ECM comprises diverse proteins, including collagens, glycoproteins and secreted proteins, which interact with cells and transmit extracellular signals, thereby altering cellular phenotypes (66). ECM remodeling alters the TME, leading to metastasis (67). In gastric cancer, Lee et al (18) reported that ELK3 promotes cancer cell spread by regulating the expression of ECM remodeling-related genes, such as bone morphogenetic protein 1 and lysyl oxidase-like 2. Lee et al (18) also demonstrated that inhibiting ELK3 can accelerate tumor cell metastasis by modulating the expression of genes associated with ECM remodeling, such as bone morphogenetic protein 1 and lysyl oxidase-like 2. Furthermore, the adhesion of tumor cells to the matrix serves a crucial role not only in cell proliferation, but also markedly contributes to the process of tumor metastasis. In breast cancer, ELK3 may act as a transcriptional activator for MT1-MMP gene expression, degrading multiple ECM components (12). Conversely, Mao et al (16) demonstrated that decreased ELK3 expression upregulates serpin family E member 1, which binds to MMPs to mediate ECM degradation; this reduces prostate cancer cell adhesion to the matrix, thereby promoting metastasis.

Further studies have indicated that ELK3 mediates epithelial-mesenchymal transition (EMT) (68,69). Li et al (70,71) demonstrated that interfering with ELK3 expression inhibits EMT in hepatocellular carcinoma cells. EMT is a critical cellular process that induces polarized epithelial cells to adopt a mesenchymal phenotype, enhancing cell motility. Cancer cells undergo EMT to detach from the primary tumor and disseminate into the bloodstream, leading to metastasis. The loss of E-cadherin, which disrupts intercellular junctions and promotes cell separation, serves as a key biomarker for EMT (72). In breast cancer research, ELK3 has been shown to suppress GATA3 expression through epigenetic mechanisms, and GATA3 promotes E-cadherin transcription (19,20). Cho et al (43) demonstrated that ELK3 directly regulates E-cadherin, and revealed that ZEB1 binds to the C-domain of ELK3, forming a protein complex that inhibits ELK3 phosphorylation activity, thereby suppressing E-cadherin expression at the transcriptional level.

EMT is driven by multiple transcription factors, which regulate the expression of classic EMT markers. These transcription factors are initiated and controlled by pathways including TGF-β signaling, Wnt/β-catenin signaling and hypoxia-inducible factor (HIF)-1α (73). Studies in pancreatic and breast cancer have demonstrated that inhibiting ELK3 affects Wnt/β-catenin and TGF-β signaling-induced EMT in tumor cells; however, the precise mechanisms remain unclear (14,19,20,74). Additionally, research has confirmed that ELK3 maintains the invasive and metastatic capabilities of liver cancer stem cells by regulating HIF-1α (75). Research by Gross et al (76) indicated that ELK3 may partially participate in prolyl hydroxylase domain (PHD) protein degradation via the E3 ligase SIAH2. PHD proteins serve as primary regulators of HIF-1α, hydroxylating HIF-1α based on intracellular oxygen levels and enabling its recognition by the E3 ligase VHL for degradation (76). In summary, ELK3 facilitates the metastasis of solid tumors by modulating ECM degradation, directly or indirectly regulating EMT, and sustaining the stemness of tumor cells.

Angiogenesis is critical for biological processes such as proliferation and development, with new blood vessels emerging from existing capillaries. In adult mammals, dysregulated angiogenesis is frequently associated with the progression of various diseases, including tumors (77). Using in situ hybridization, Ayadi et al (78) detected ELK3 expression in sites of angiogenesis and vasogenesis within mouse bladder vessels, cardiac endothelium and the dorsal aorta, providing evidence of its involvement in vascular development. Angiogenesis comprises three steps: Endothelial cell activation, endothelial cell proliferation and migration, and maturation of newly formed vessels. The transition of endothelial cells to an angiogenic phenotype is induced by soluble factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). One of the most potent activators is VEGF, an endothelial cell-specific mitogen that serves a central role in neovascularization (79). Molecular studies by Mou et al (80) revealed that ELK3 enhances VEGF-A expression and secretion by promoting HIF-1α ubiquitination and degradation, ultimately promoting glioma angiogenesis. In vivo and in vitro studies by Zheng et al (81) demonstrated that Ras can phosphorylate ELK3, leading to increased activity in the VEGF promoter region (−80 to −53) and elevated expression, indicating its decisive role in angiogenesis. Conversely, Heo et al (82) observed that VEGF may influence ELK3 expression at the protein level, potentially through modulating MAPK signaling activity. FGF-2 can also induce ELK3 phosphorylation via an ERK-1/2-dependent pathway, converting ELK3 into an activator of angiogenesis (81). An additional report has indicated that VEGF expression exhibits no marked changes in retinal vessels in ELK3-knockout mouse models, whereas the RNA expression levels of Tie receptors for angiopoietin, Tie1 and Tie2, are markedly reduced. It was subsequently revealed that Tie2 expression gradually recovers to normal levels with mouse growth, whereas Tie1 expression remains downregulated; this may reflect the involvement of ELK3 in the transcriptional regulation of Tie1 (83). The aforementioned studies collectively demonstrate that ELK3 promotes angiogenesis. However, an in vitro study has also suggested that ELK3 recruits the co-repressor Sin3A to inhibit ETS1 activity, leading to dysregulation of MT1-MMP transcription and reduced angiogenic capacity in human umbilical vein endothelial cells (84). Although this contradicts the other findings, based on the mechanism of ELK3 activation, this discrepancy may arise from variations in specific experimental conditions and cell types affecting ELK3 function.

The cellular environment surrounding tumor cells is termed the TME, which is composed of cellular and non-cellular components. These primarily include diverse types of stromal cells (tumor-associated fibroblasts, lymphocytes, macrophages and endothelial cells), immune cells (for example, T and B lymphocytes) and extracellular components (including cytokines, growth factors, hormones and ECM components). These elements envelop tumor cells and are nourished by the surrounding tumor vasculature. Matrix cells within the TME promote tumor growth by directly activating growth signals in tumor cells or remodeling the surrounding area through the release of various molecules (85). Concurrently, they enhance critical biological processes such as tumor heterogeneity, adaptability and evasion of immune surveillance (86–89). Consequently, cells within the TME have emerged as targets for effectively suppressing cancer. Tumor-associated lymphatic vessels (TALVs), composed of lymphatic endothelial cells, constitute a major component of the TME; due to their higher permeability compared with blood vessels, TALVs serve a particularly crucial role in tumor dissemination and metastasis (90). Research by Kim et al (15) demonstrated that ELK3 promotes the viability of tumor-associated lymphatic endothelial cells and enhances their capacity to stimulate breast cancer proliferation. Furthermore, Wang et al (38) revealed through bioinformatics analysis that the abnormally high expression of ELK3 in tumor cells is closely associated with the VEGF-C/VEGF receptor (VEGFR)-3 axis. Conversely, Park et al (59) reported that suppressing ELK3 expression in TALVs can lead to decreased VEGFR-3 expression. The protein encoded by VEGF-C promotes angiogenesis and endothelial cell proliferation by binding to and activating VEGFR-2 and VEGFR-3. Oh et al (91) explored the potential mechanism by which ELK3 regulates the VEGF-C/VEGFR-3 axis. ELK3 was shown to induce elevated levels of phosphorylated and acetylated NF-κB in lymphatic endothelial cells, which may subsequently promote upregulation of VEGFC expression. Furthermore, ELK3 expression in gastric cancer has been reported to promote the infiltration of tumor-associated M2 macrophages (38). Macrophages are the most abundant infiltrating immune cells in the TME, participating in tumor cell aerobic glycolysis, proliferation and other biological processes that drive malignant progression. However, the mechanism by which ELK3 regulates macrophages remains unclear.

The majority of current investigations into ELK3-mediated regulation of the TME center primarily on the mechanisms underlying ECM remodeling, lymphangiogenesis and angiogenesis. However, Yang et al (92) reported that ELK3 participates in the development and differentiation of immune cells, and a previous study indicated that ELK3 is a key regulator of natural killer (NK) cell therapy response in triple-negative breast cancer (93). Highly expressed in triple-negative breast cancer, ELK3 acts as a core regulator by modulating mitochondrial dynamics to influence NK cell cytotoxicity; knocking down ELK3 has been shown to enhance NK cell antitumor activity (94). Jung et al (95) further elucidated the molecular mechanism of ELK3-based immunotherapy. Depletion of ELK3 was shown to increase CXCL16 expression, which in turn can mediate chemotaxis to recruit NK cells, thereby amplifying NK cell cytotoxicity. This process ultimately enhances the antitumor immune response, further solidifying ELK3 as a potential therapeutic target for TNBC (95).

Chemotherapy resistance in tumor cells leads to cancer recurrence and metastasis, constituting a notable factor affecting the quality of life and clinical prognosis of patients with cancer, and a major obstacle in cancer treatment. Current molecular mechanisms of tumor chemotherapy resistance include abnormal activation of ABC transporters, mitochondrial alterations, DNA repair, autophagy, EMT, cancer stemness and exosomes (96). Wang et al (38) demonstrated that high ELK3 expression counteracts the anticancer effects of axitinib. In a clinical study, Lee et al (97) revealed that elevated ELK3 levels in prostate cancer tissues leads to decreased SPOP expression. Docetaxel induces cell death through SPOP-mediated degradation of ELK3, whereas SPOP deletion or mutation confers docetaxel resistance in prostate cancer cells. This indicates that SPOP mutations may promote tumor cell resistance by affecting ELK3 stability, suggesting a novel therapeutic pathway for SPOP-positive prostate cancer. Furthermore, studies have indicated that ELK3 promotes tumor stemness and resistance to oxaliplatin (48,98). When chemotherapy drugs stimulate tumor cells, autophagy-related signaling pathways are activated and autophagy levels are elevated; this enables tumor cells to degrade chemotherapeutic agents, enhancing their resistance to chemotherapy (99). Park et al (100) elucidated the potential mechanism by which ELK3 promotes resistance: Inhibiting ELK3 expression was shown to disrupt autophagy mediated by the PI3K/Akt/mTOR pathway, thereby restoring sensitivity to doxorubicin chemotherapy in breast cancer cells. Another study revealed that ELK3 determines chemotherapy sensitivity to cisplatin in triple-negative breast cancer cells by regulating mitochondrial dynamics. Therefore, inhibiting ELK3 expression holds promise as a potential therapeutic strategy to overcome chemotherapy resistance or induce sensitivity in triple-negative breast cancer (10). Wang et al (101) discovered that ELK3 transcriptionally upregulates SERPINE1, which inhibits the ubiquitination of PCBP2, which restricts ferroptosis and consequently induces gefitinib resistance in lung cancer. In ovarian cancer, ELK3 has been verified to function as a transcriptional repressor; it downregulates tropomyosin-2 protein expression to activate YAP1 signaling, thereby resulting in cisplatin resistance (102). Furthermore, experiments by Peng et al (103) confirmed that ELK3 suppresses CHD4 expression and mediates the cisplatin-resistant phenotype. Collectively, available evidence indicates that ELK3 drives tumor chemoresistance through three key mechanisms: Promoting cancer stemness, triggering autophagy and modulating mitochondrial dynamics.