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Tumor Discovery WDR4 in cancer

2.1.1. RNA modification and tumorigenesis Figure 2 illustrates the molecular mechanisms of WDR4

WDR4’s role in RNA metabolism is particularly evident in tumorigenesis.
in its involvement in M7G modification of tRNA, which 2.2. Regulation of cell cycle and apoptosis
stabilizes tRNA molecules and improves translation
fidelity. Dysregulation of this modification in cancer WDR4’s influence on cell cycle progression and apoptosis
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cells contributes to rapid protein synthesis, supporting is fundamental to its role in tumorigenesis. Through
the increased cellular proliferation and metabolic interactions with cell cycle regulators and apoptotic
demand associated with tumorigenesis. In HCC, pathways, WDR4 promotes cell proliferation while
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WDR4 overexpression has been shown to enhance m7G inhibiting programmed cell death, creating a cellular
modification, resulting in the translation of oncogenic environment conducive to tumor growth.
proteins that promote cell survival and proliferation. By 2.2.1. Cell cycle control
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specifically improving the translation efficiency of these
tumor-promoting proteins, WDR4 drives cellular processes In several types of cancer, WDR4 overexpression is
that support malignancy, highlighting its potential as an associated with increased levels of cell cycle-promoting
oncogene in RNA metabolism. proteins, particularly those that regulate the G1/S
transition. 32,33 In lung cancer, WDR4’s impact on cyclin
2.1.2. Interaction with the ubiquitin-proteasome system D1 levels accelerates cell cycle progression by promoting
WDR4 also interacts with the ubiquitin-proteasome system, the G1/S phase transition, enabling tumor cells to sustain
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influencing protein stability by promoting the degradation high proliferation rates. In addition, WDR4’s influence
of tumor suppressor proteins. For instance, in cancer, on other cyclins and cyclin-dependent kinases may further
WDR4 facilitates the ubiquitination and degradation of p53, reinforce its role in cell cycle regulation, contributing to
a crucial tumor suppressor, enabling cancer cells to evade continuous tumor growth.
apoptosis. This ability to degrade tumor suppressors while 2.2.2. Modulation of apoptosis
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stabilizing cell cycle regulators allows WDR4 to support
cell proliferation and survival, which are critical for tumor WDR4’s role in apoptosis resistance is evident in its
progression. WDR4-mediated ubiquitination of protein interactions with pro- and anti-apoptotic factors. 35,36 In head
tyrosine phosphatase, non-receptor type 23 (PTPN23) and neck squamous cell carcinoma, WDR4 downregulates
leads to its proteasomal degradation, thereby inhibiting or degrades p53, reducing cellular sensitivity to apoptosis-
the lysosomal transport and degradation of wild-type inducing signals. Furthermore, WDR4 is associated with
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epidermal growth factor receptor (EGFR), EGFR mutants, the upregulation of anti-apoptotic proteins, such as BCL-2,
and c-MET. Through this mechanism, WDR4 maintains which inhibit apoptotic signaling pathways and protect
EGFR and c-MET signaling, promoting the proliferation, cancer cells from programmed cell death. 36,37 This ability
migration, invasion, stemness, and metastasis of non- to modulate apoptosis is essential for cancer cell survival,
small cell lung cancer. In addition, WDR4-mediated particularly under stress conditions, such as nutrient
ubiquitination of promyelocytic leukemia (PML) enhances deprivation or exposure to chemotherapy. 38,39 Figure 3
lung tumor growth. Specifically, the degradation of PML illustrates the molecular mechanisms underlying the
induced by WDR4 triggers the secretion of a series of cell inhibitory effects of WDR4 on the cell cycle and apoptosis
surface or secreted factors, including CD73, urokinase- of cancer cells.
type plasminogen activator receptor, and serum amyloid
A2, which initiate paracrine signaling that stimulates cell 3. WDR4 is associated with multiple
migration, invasion, and metastasis. WDR4-induced oncogenic pathways
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ubiquitination and degradation of Arhgap17 activate 3.1. PI3K/AKT/mTOR pathway
Rac1, which prevents the cell cycle exit of granule neuron
precursor (GNP), thus supporting GNP proliferation and The PI3K/AKT/mTOR signaling pathway is a crucial
ultimately facilitating cell cycle progression, a process intracellular regulatory network that plays a key role in
essential for cerebellar development and motor function. regulating fundamental biological processes such as cell
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By modulating the ubiquitin-proteasome pathway, WDR4 growth, proliferation, survival, metabolism, and motility.
effectively tilts the balance between cell survival and Abnormal activation of this pathway is closely associated
apoptosis in favor of tumor progression. However, current with the development of various diseases, particularly
research suggests that WDR4’s role in protein degradation cancer, diabetes, and neurodegenerative diseases. 40-42 PI3K
might be interconnected with its function in tRNA (phosphoinositide 3-kinase) is an enzyme that catalyzes
modification, although the exact mechanisms may differ. the phosphorylation of phosphoinositides and their

Volume 4 Issue 1 (2025) 39 doi: 10.36922/td.5830