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Tumor Discovery WDR4 in cancer

In liver cancer, studies have shown that WDR4 during embryogenesis, tissue development, and wound
may regulate the protein level of CCNB1, influencing healing, and plays a significant role in cancer metastasis. 61,62
the activation of the PI3K/AKT signaling pathway In nasopharyngeal carcinoma, the expression of WDR4
and promoting tumor progression. In head and neck is significantly elevated, leading to a notable increase in the
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squamous cell carcinoma, it has been found that m7G translation efficiency of m7G-modified codon-containing
tRNA modification mediates the interaction with the PI3K/ mRNA. This enhanced translation efficiency activates the
AKT/mTOR pathway, regulating the mRNA expression WNT/β-catenin signaling pathway, thereby influencing
profile and further promoting cancer progression. This the EMT process. 63
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suggests the significant role of tRNA modifications in
tumor metabolism and biological processes. In addition, 3.4. EGFR pathway
in esophageal squamous cell carcinoma, WDR4 regulates The EGFR pathway is a critical cellular signaling pathway
m7G modification to affect tRNA expression, activating that plays a fundamental role in regulating biological
the RPTOR/ULK1/autophagy pathway and contributing to processes such as cell proliferation, survival, migration,
cancer development. These findings indicate that WDR4, and differentiation. EGFR is a transmembrane receptor
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as a critical regulatory factor, plays a significant role in belonging to the receptor tyrosine kinase family. 64-66
the onset and progression of various cancers through its
regulation of the PI3K/AKT/mTOR signaling pathway. In addition to its regulation through the E3 ubiquitin
ligase-mediated degradation of PTPN23, as previously
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3.2. MAPK pathway discussed, WDR4 has been shown to influence tRNA
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The mitogen-activated protein kinase (MAPK) pathway modification by regulating the M7G cap in HCC. This
is a critical intracellular signaling pathway involved tRNA modification enhances resistance to lenvatinib, a
in various physiological processes, including cell first-line tyrosine kinase inhibitor used in the treatment
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growth, differentiation, stress response, apoptosis, and of advanced liver cancer. Specifically, WDR4 promotes
metabolism. 47,48 The activation of the MAPK pathway is the translation of genes involved in the EGFR signaling
typically triggered by external stimuli such as growth factors, pathway, contributing to the development of drug
cytokines, and environmental stress. On activation, this resistance.
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pathway regulates downstream transcription factors and Furthermore, in bladder cancer, WDR4, in collaboration
other effector molecules, thereby influencing the function with METTL1, modulates tRNA modifications to regulate
and fate of the cell. 50-52 the translation of EGFR and EGF-containing fibulin-like
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In pancreatic cancer, the MAPK pathway plays a extracellular matrix protein 1 (EFEMP1). This process
significant role in regulating cell proliferation and survival. activates the EGFR signaling pathway, emphasizing
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The functional role of WDR4 in influencing protein stability the significant role of tRNA modifications and their
may extend to the components of the MAPK pathway, interaction with key oncogenic signaling pathways in
thereby enhancing their stability and facilitating their cancer progression and drug resistance. Figure 4 illustrates
activation. By modulating MAPK signaling, WDR4 supports the key role of WDR4 in the pathway.
tumor cell growth and metastasis, positioning it as a potential 4. Clinical implications and therapeutic
therapeutic target in MAPK-driven pancreatic cancer.
potential of WDR4
3.3. WNT/β-catenin pathway and epithelial- 4.1. WDR4 as a prognostic and predictive biomarker
mesenchymal transition (EMT) pathway
Elevated WDR4 expression across multiple cancers
The WNT/β-catenin pathway is a central signaling correlates with poor clinical outcomes, underscoring its
mechanism that regulates various physiological processes, potential as a prognostic and predictive biomarker. High
including development, stem cell maintenance, and tissue levels of WDR4 expression in patient samples correlate with
homeostasis. 50,54 Dysregulation of this pathway is a key feature increased metastasis, reduced survival rates, and resistance
in the pathogenesis of many diseases, particularly cancer. 55,56 to standard therapies, suggesting its use as a biomarker for
The EMT is a biological process in which epithelial assessing tumor aggressiveness and therapeutic resistance.
cells, which are normally tightly bound and organized
in layers, lose their cell-cell adhesion properties and 4.2. Therapeutic targeting of WDR4
acquire mesenchymal characteristics. 57-59 These include Several approaches are applied to target WDR4’s oncogenic
increased motility, invasiveness, and the ability to degrade activity, including small-molecule inhibitors, RNA
components of the extracellular matrix. EMT is essential interference, gene editing, and combination therapies.
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Volume 4 Issue 1 (2025) 41 doi: 10.36922/td.5830