This editorial refers to "Myc-associated zinc finger protein drives colorectal cancer metastasis through activating ubiquitin like with ring finger protein one" by Mao et al, 2025; https://dx.doi.org/10.4251/wjgo.v17.i11.109481.
INTRODUCTION
Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, primarily due to metastasis to the liver, lungs, and other organs[1-3]. Despite advances in surgery, chemotherapy, and targeted treatments (such as anti-epidermal growth factor receptor and anti-vascular endothelial growth factor therapies), the long-term prognosis for metastatic CRC remains poor: Five-year survival rates are only about 10%-14%[1,4-6]. Clearly, new therapeutic strategies are necessary. In recent issue of the World Journal of Gastrointestinal Oncology, an intriguing study by Mao et al[7] explores a novel epigenetic signaling pathway involving Myc-associated zinc finger protein (MAZ), ubiquitin-like with PHD and RING finger domains 1 (UHRF1), and esophageal cancer-related gene 4 (ECRG4). Their findings describe the MAZ/UHRF1/ECRG4 axis that promotes CRC invasion and metastasis, highlighting its potential as a targetable vulnerability in metastatic CRC[3].
MAZ: A TRANSCRIPTIONAL DRIVER OF CANCER PROGRESSION
MAZ is a zinc-finger transcription factor initially identified through its interaction with the c-Myc promoter[8,9]. It is broadly expressed and frequently overexpressed in cancers[8]. Recent research has recognized MAZ as a pro-tumorigenic factor in various cancers, with roles in cell proliferation, angiogenesis, and metastasis[3,8,10]. For instance, in hepatocellular carcinoma, MAZ expression is increased and correlates with distant metastasis; reducing MAZ levels inhibits cancer cell growth, invasion, and migration, partly by reversing an epithelial-mesenchymal transition (EMT) gene signature[10]. Similarly, in melanoma and glioblastoma, MAZ has been shown to transcriptionally activate oncogenic target genes (such as NDUFS3 in melanoma), thereby promoting tumor progression[11]. In breast, prostate, and pancreatic cancers, MAZ’s regulation of MYC and Ras pathways suggests it is a key transcription factor utilized by cancer cells for growth and eventual spread[8].
In the context of gastrointestinal malignancies, MAZ is emerging as an important regulator of the tumor microenvironment and inflammation[7]. Triner et al[12] demonstrated that MAZ is highly upregulated in ulcerative colitis and colitis-associated colon cancer, where it amplifies proinflammatory STAT3 signaling. Overexpression of MAZ in intestinal epithelial cells led to heightened STAT3 activation, increased inflammation-induced tumorigenesis, and enhanced growth of human CRC xenografts[12]. This confirms that MAZ can drive not only intrinsic tumor cell pathogenesis but also inflammatory pathways that indirectly promote cancer progression. Notably, STAT3 is a known promoter of CRC invasion and immune evasion, suggesting one mechanism by which MAZ might facilitate metastasis[13]. Therefore, MAZ has dual oncogenic roles; boosting proliferative signals like STAT3 and, as Mao et al[7] now show, activating an epigenetic silencing program that further precipitates metastatic potential[13].
UHRF1: EPIGENETIC ENABLER OF METASTASIS
UHRF1 is a multi-domain epigenetic regulator that recruits DNA methyltransferase 1 (DNMT1) to hemimethylated DNA during replication, thereby propagating DNA methylation and silencing tumor suppressor genes (TSGs)[14,15]. UHRF1 is frequently overexpressed in solid tumors, including CRC, and is generally associated with aggressive disease. Wang et al[16] identified UHRF1 as upregulated in approximately 80% of CRCs, with higher levels linked to lymph node positivity, distant metastasis, and advanced Dukes stage. Functionally, depleting UHRF1 in CRC cell lines reduced proliferation and migration, while increasing apoptosis and G0/G1 arrest[16]. Mechanistically, the study attributed UHRF1’s oncogenic effect partly to the silencing of the cell cycle inhibitor p16 INK4A[16]. Therefore, UHRF1 can promote tumor progression by epigenetically repressing TSGs that normally regulate cell growth and survival.
Importantly, growing evidence links UHRF1 to the metastatic nature of cancers. In colon cancer cells, UHRF1 is a downstream target of Wnt/β-catenin-c-Myc signaling, and its upregulation is necessary for silencing TUSC3, a metastasis-suppressor gene[17-19]. Disruption of this UHRF1-mediated silencing restored TUSC3 expression and reduced cell invasiveness[17]. More broadly, a recent study showed that genetic disruption of UHRF1’s chromatin-reading domains in CRC cells caused DNA demethylation, reactivation of multiple suppressed TSGs, and a significant reduction in tumor growth and metastasis in vivo[14]. In other words, UHRF1 is essential not only for primary tumor growth but also for maintaining the epigenetic program that supports metastatic colonization[14]. Collectively, these findings confirm UHRF1 as a promising therapeutic target: Targeting the UHRF1/DNMT1 axis can reactivate dormant tumor suppressors and decrease malignancy[14,20].
ECRG4: A SILENCED METASTASIS SUPPRESSOR
ECRG4 is a lesser-known player highlighted by Mao et al[7]. First identified in esophageal cancer, ECRG4 encodes a secreted protein involved in inflammation and cell growth. In various cancers, ECRG4 functions as a novel tumor suppressor gene that is often downregulated by epigenetic mechanisms[21]. Götze et al[21] reported that the ECRG4 promoter is frequently hypermethylated in CRC and gliomas, with methylation strongly linked to the loss of ECRG4 mRNA[22]. Treating CRC cells with the DNA demethylating agent 5-aza-2′-deoxycytidine reactivated ECRG4 expression, confirming that DNA methylation directly silences this gene[21]. Functional assays show that ECRG4 has tumor-inhibitory effects: Restoring ECRG4 in CRC cells significantly reduces proliferation and colony formation, induces apoptosis, and decreases tumor growth in mice[23]. Conversely, loss of ECRG4 correlates with more aggressive cancer behavior. Tissue analyses from clinical samples reveal that ECRG4 expression is notably lower in CRC tumors compared to normal colon tissue, and low ECRG4 levels are associated with poor differentiation and a higher incidence of lymph node metastasis[23]. In summary, ECRG4 appears to limit the invasive and metastatic potential of CRC.
One intriguing aspect of ECRG4 biology is that it encodes a factor that can be secreted or membrane-bound, influencing the tumor microenvironment. For example, adding recombinant ECRG4 protein to culture media has been shown to suppress colon cancer cell growth, similar to the effects of re-expressing the ECRG4 gene[21]. This suggests that ECRG4’s normal role may involve paracrine signaling that regulates local inflammation and cell movement – functions that are lost when ECRG4 is epigenetically silenced[24]. In fact, studies in esophageal cancer models indicate that ECRG4 can recruit immune cells and modify cytokine networks to oppose tumor growth[25,26]. Therefore, silencing ECRG4 in CRC may create a more permissive environment for tumor invasion, driven by both cell-intrinsic and microenvironmental mechanisms.
MAZ–UHRF1–ECRG4: LINKING TRANSCRIPTIONAL ACTIVATION TO EPIGENETIC SILENCING
The study by Mao et al[7] connects these elements into a clear signaling pathway (Figure 1). They identify MAZ as an upstream transcriptional activator of UHRF1 in CRC. Using promoter analyses and gene expression studies, Mao et al[7] show that MAZ binds to the UHRF1 promoter, promoting UHRF1 transcription and increasing its protein levels. This aligns with MAZ’s known preference for GC-rich promoter regions[8]; notably, the UHRF1 promoter is CpG-rich and may be regulated by zinc-finger transcription factors like MAZ. By identifying MAZ as a positive regulator of UHRF1, the authors establish a direct link between a Myc-associated transcription factor and an epigenetic silencer protein in CRC. This presents a new insight. While c-Myc was already known to induce UHRF1 expression in colon cancer, MAZ provides a different transcriptional input to UHRF1, potentially integrating signals from oncogenic pathways (such as Ras/MAPK or inflammatory pathways) into the cancer cell's epigenetic landscape[7,17].
Figure 1 Metastatic outcomes following activation of the Myc-associated zinc finger protein-Ubiquitin-like with PHD and RING finger domains 1-esophageal cancer-related gene 4 axis.
Myc-associated zinc finger protein binds to the Ubiquitin-like with PHD and RING finger domains 1 promoter, activating transcription and downstream protein synthesis. Ubiquitin-like with PHD and RING finger domains 1, directly or indirectly, then leads to hypermethylation of esophageal cancer-related gene 4, thereby decreasing its expression. This culminates in a metastatic transition governed by epithelial-mesenchymal transition-induced changes within the tumor microenvironment. ECRG4: Esophageal cancer-related gene 4; EMT: Epithelial-mesenchymal transition; MAZ: Myc-associated zinc finger protein; UHRF1: Ubiquitin-like with PHD and RING finger domains 1.
Downstream, Mao et al[7] demonstrate that increased UHRF1 (driven by MAZ) causes epigenetic silencing of ECRG4 (Figure 1). Chromatin immunoprecipitation and methylation assays in the study show that UHRF1, either directly or indirectly, promotes hypermethylation of the ECRG4 promoter, thereby shutting down ECRG4 expression[7]. The loss of ECRG4, in turn, removes a restraint on metastasis: CRC cells with the active MAZ-UHRF1-ECRG4 axis display molecular signs of EMT and have greater invasive and metastatic potential in experimental models (Figure 1). Mao et al[7] report that knocking down MAZ or UHRF1 leads to re-expression of ECRG4, along with increased epithelial markers and decreased mesenchymal markers, resulting in reduced cell migration and invasion. Taken as a whole, MAZ binds to the UHRF1 promoter to boost UHRF1 transcription; elevated UHRF1 then recruits DNMT1 to the ECRG4 promoter, leading to DNA hypermethylation and ECRG4 repression[7]. The silencing of this secreted tumor suppressor relieves CRC cells of their restraints, enabling EMT, basement membrane invasion, and eventual metastatic spread[7,27].
Mechanistically, Mao et al[7] position MAZ upstream of UHRF1-dependent silencing of ECRG4, a shift that plausibly facilitates EMT by promoting loss of epithelial junctional integrity (i.e., reduced E-cadherin-mediated adhesion), cytoskeletal reprogramming (vimentin upregulation), and acquisition of motility and invasiveness programs driven by EMT transcription factors such as SNAIL (a zinc finger transcription factor)[27-29]. This axis may intersect with major EMT-inducing networks that are highly relevant to CRC metastasis: (1) Transforming growth factor-beta signaling (a core EMT inducer through SMAD-dependent transcriptional remodeling); (2) Wnt/β-catenin signaling (a central CRC pathway that can reinforce EMT and is linked to UHRF1 regulation in colon cancer contexts); and (3) STAT3 signaling[27,28,30,31]. MAZ transcriptionally amplifies STAT3 in colitis and colon cancer models, promoting invasion and immune evasion, offering a plausible upstream synergy that could further bias cells toward EMT[12,32]. The MAZ-UHRF1-ECRG4 axis can be viewed as an epigenetic enabler of EMT circuits, connecting this novel molecular axis with an already established component of metastatic biology[27].
It is noteworthy that this single axis links multiple layers of regulation: (1) The transcription factor MAZ; (2) The epigenetic regulator UHRF1; and (3) The secreted tumor suppressor ECRG4. Each component has already been individually implicated in cancer progression, but Mao et al[7] combine them into a linear pathway that drives metastasis. This MAZ/UHRF1/ECRG4 cascade illustrates how oncogenic transcriptional programs interact with the epigenome to turn off metastasis suppressors. It also emphasizes communication between cancer cell-intrinsic changes (such as DNA methylation) and tumor-extrinsic factors (such as secreted proteins and EMT-related remodeling)[7]. This multifactorial nature may explain why metastasis is challenging to treat, while at the same time offering multiple potential intervention points to prevent metastasis.
THERAPEUTIC AND TRANSLATIONAL IMPLICATIONS
The details of the MAZ-UHRF1-ECRG4 axis open new translational opportunities. Targeting this pathway could inhibit metastasis at the epigenetic level, complementing existing therapies that target oncogenic signaling or angiogenesis[4,5,20].
Restoring ECRG4 expression
Since ECRG4 is silenced by promoter methylation, epigenetic drugs might be used to reactivate its expression. DNA methyltransferase inhibitors, such as 5-azacytidine or decitabine, are already employed clinically for hematologic malignancies, and preclinical studies show they can induce ECRG4 in CRC cells[21,33]. By demethylating the ECRG4 promoter, these agents could restore ECRG4’s anti-metastatic effects. An alternative approach is ECRG4 replacement therapy – since ECRG4 is secreted, recombinant ECRG4 protein or a related agonist could be administered. The feasibility of this approach is supported by in vitro experiments demonstrating that exogenous ECRG4 protein inhibits colon cancer cell growth[21]. In theory, restoring ECRG4 in the tumor microenvironment could suppress invasion, potentially by modulating immune cell recruitment and reducing EMT-inducing signals[24]. Of course, much work remains to translate this concept into practice, including identifying the biologically active form of ECRG4 and developing optimal delivery methods[7].
Targeting UHRF1
UHRF1 is a promising drug target because of its central role in maintaining oncogenic DNA methylation. A 2025 study by Bai et al[14] showed that a peptide mimetic of the mouse protein STELLA can selectively block UHRF1’s chromatin binding, leading to strong demethylation of tumor suppressors and reducing CRC tumor growth in mice. By using a lipid nanoparticle to deliver mRNA that encodes this peptide, they effectively disrupted UHRF1’s function, resulting in reactivation of silenced genes and decreased tumorigenicity[14]. This proof-of-concept demonstrates that UHRF1’s epigenetic activity can be pharmacologically halted, offering a strategy to prevent metastasis[34]. Targeting UHRF1 could reverse the methylation-silencing of ECRG4 and other metastasis suppressors simultaneously[34]. It is encouraging that UHRF1 inhibition mimics UHRF1 knockdown, which has been shown to hinder metastasis in CRC models[14]. Overall, targeting the UHRF1/DNMT1 axis presents a new anti-metastatic approach that is now approaching feasibility.
Inhibiting MAZ or its upstream pathways
Transcription factors like MAZ are traditionally difficult to target directly, but there may be indirect methods to modulate their activity. MAZ has been identified as a mediator of STAT3-driven colon tumorigenesis. Therefore, JAK/STAT pathway inhibitors (currently in trials for solid tumors) might reduce some MAZ-related effects[12,13,35]. Additionally, MAZ’s expression could be decreased by targeting signals that induce it, such as hypoxic or inflammatory signals in the tumor microenvironment, since MAZ has been shown to participate in hypoxia-driven inflammation in CRC[36]. Another potential approach is using decoy oligonucleotides to block MAZ’s DNA-binding sites, as has been done for other oncogenic transcription factors. Any intervention targeting MAZ would need careful evaluation, considering its normal roles in gene regulation. Nonetheless, the idea of dual targeting MAZ and UHRF1 is compelling: By lowering MAZ activity and inhibiting UHRF1, clinicians might both reduce the oncogenic drive and directly lift epigenetic repression of metastasis suppressors like ECRG4. Unlike epidermal growth factor receptor or vascular endothelial growth factor inhibitors, which mainly impact primary tumor growth and angiogenesis, targeting the MAZ/UHRF1/ECRG4 pathway would specifically aim to prevent the epigenetic promotion of metastasis – a complementary mechanism that could potentially lower metastatic relapse when combined with standard treatments[4,5].
Biomarker panel proposal
A pragmatic translational extension is to propose a risk-stratification biomarker panel in which a high MAZ, high UHRF1, and low ECRG4 (or ECRG4 hypermethylation) identify a metastasis-prone environment[22]. Clinically, this triad could be operationalized as: MAZ/UHRF1 immunohistochemistry on primary tumor biopsy or resection specimen, paired with ECRG4 methylation testing to estimate metastasis risk and, potentially, to select patients most likely to benefit from epigenetic therapies or future UHRF1-directed agents, ultimately aligning biomarker selection with mechanism[24,30]. Patient selectivity can be enhanced through clinical examination. UHRF1 overexpression in CRC has been associated with aggressive clinicopathologic features, including lymph node positivity, distant metastasis, and advanced stage, while ECRG4 is frequently silenced through hypermethylation in CRC and linked to reduced tumor suppressive capabilities[16,21,23]. These characteristics may allow specific panels to be provided for patients, streamlining treatment in previously treatment-resistant CRC[22].
It is important to note that translating these findings to the clinic will require additional validation and may present its own set of clinical challenges as scientists target this axis. Translationally, each node of the MAZ-UHRF1-ECRG4 axis raises distinct, addressable clinical concerns. The DNA-binding interfaces and pleiotropic physiologic roles of MAZ complicate specificity and toxicity, making direct targeting of MAZ more challenging. However, multiple approaches – such as protein-protein interaction inhibitors and degradation inducers – are increasingly applied to oncogenic transcription factors[14,37]. For UHRF1, specificity is the key issue, since epigenetic regulators coordinate the normal maintenance of the methylome. Recent work has demonstrated ortholog-informed inhibition strategies that disrupt UHRF1 function in vivo[30]. This demonstrates the conceptual feasibility of domain-selective inhibition, whereby UHRF1’s chromatin-reading domains are required for the maintenance of CRC-specific methylation and oncogenic properties. ECRG4 functional restoration via DNA-methyltransferase inhibitors must contend with global demethylation (i.e., off-target gene reactivation, cytopenias, and nonselective epigenomic effects), a substantiated limitation of some hypomethylating agents[38]. Lastly, recombinant protein replacement strategies for secreted tumor suppressors face typical constraints in protein therapeutics: (1) Proteolysis; (2) Tumor penetration; and (3) Dosing frequency[39].
Preliminary data suggest MAZ and UHRF1 are frequently upregulated in advanced CRC, and ECRG4 is often silenced, but patient stratification would be necessary; perhaps high MAZ/UHRF1 and low ECRG4 could serve as a molecular signature of aggressive, metastasis-prone CRC[12,16,21]. Additionally, the potential off-target effects of epigenetic therapies must be considered[33]. Broadly reactivating gene expression could lead to unintended consequences; therefore, a targeted approach (such as the STELLA peptide, which specifically disrupts UHRF1’s oncogenic function) might be preferable to global demethylation[14]. Fortunately, the ongoing development of epigenetic inhibitors and delivery systems is making it more feasible to test these strategies in vivo.
CONCLUSION
The MAZ/UHRF1/ECRG4 signaling axis exemplifies how transcriptional and epigenetic dysregulation work together to promote CRC metastasis. By increasing UHRF1 expression, MAZ initiates an epigenetic silencing process that turns off ECRG4 and probably other genes that inhibit growth, thereby boosting EMT, invasion, and metastasis. The study by Mao et al[7] explains this harmful mechanism and highlights its translational potential: Targeting this axis could provide a new approach to treating metastasis at the molecular level. Given the very poor outcomes linked to CRC, an epigenetic method aimed at maintaining DNA methylation (through UHRF1) or restoring lost tumor suppressors (like ECRG4) could address a critical need[7,34]. In summary, the MAZ-UHRF1-ECRG4 pathway is a key mechanism driving metastatic CRC that needs further investigation[7]. Restoring the function of silenced genes like ECRG4, or inhibiting their silencers, could help prevent cancer cells from metastasizing. This study provides strong support for this idea. With ongoing research, this scientific finding could lead to effective anti-metastatic treatments for CRC patients.
Peer review: Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: United States
Peer-review report’s classification
Scientific quality: Grade A
Novelty: Grade B
Creativity or innovation: Grade B
Scientific significance: Grade B
P-Reviewer: Wen HM, PhD, Post Doctoral Researcher, United States S-Editor: Luo ML L-Editor: A P-Editor: Wang CH
