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Tumor Discovery WDR4 in cancer

Figure 1. The protein structure of WDR4. WDR4 is composed of multiple WD40 domains
Abbreviations: WDR4: WD repeat domain 4.
that contributes to essential processes in normal cellular tumor progression, metastasis, and poor patient prognosis.
function and disease states, including transcriptional In HCC, high expression of WDR4 is associated with
regulation, signal transduction, protein degradation, and aggressive disease features, including advanced tumor stage
cell cycle progression. 2 and reduced survival, as it supports RNA modifications that
Functionally, WDR4 plays a pivotal role in RNA promote the synthesis of oncogenic proteins by forming a
metabolism, particularly in m7G modification of transfer complex with methyltransferase like 1 (METTL1), which
RNA (tRNA). This post-transcriptional modification is cooperatively regulates the m7G modification of mRNA
3
critical for stabilizing tRNA, enhancing translation fidelity, in HCC cells. WDR4 effectively modulates both the
and ensuring efficient protein synthesis. In the biological expression of mRNA and the protein levels of the METTL1
4,5
characteristics of malignant tumor cells, the stability of gene. Moreover, the impact of WDR4 on tRNA m7G levels
RNA molecules and the efficiency of their translation directly mediates the translation of TRIM28, which in turn
processes constitute the fundamental mechanisms driving enhances the stemness of cancer stem cells. This process
the rapid proliferation and growth of cancer cells. By contributes to the development of resistance to lenvatinib
modulating tRNA methylation, WDR4 affects RNA and promotes tumor progression in HCC. In lung cancer,
stability and translation efficiency, driving the increased WDR4 has been shown to influence cell cycle regulation
protein synthesis required for oncogenesis. Consequently, and apoptosis, facilitating rapid cell division and enhanced
6,7
the dysregulation of WDR4 leads to a cellular environment survival under conditions of cellular stress. Similarly,
conducive to tumorigenesis, positioning WDR4 as a in head and neck squamous cell carcinoma, elevated
significant factor in malignant transformation. 8,9 expression of WDR4 is linked to disease progression by
regulating RNA translation through RNA modification.
In addition to its role in RNA modification, recent studies This process impacts critical signaling pathways, including
have shown that WDR4 regulates protein stability through the PI3K/AKT/mTOR pathway, which are essential for
10
interactions with the ubiquitin-proteasome system. promoting oncogenic protein synthesis. This regulation
20
Specifically, WDR4 facilitates the degradation of tumor facilitates tumor growth and may contribute to the
suppressor proteins and enhances the stability of proteins aggressive behavior characteristic of this malignancy.
involved in cell cycle progression and resistance to apoptosis.
11
This mechanism may promote tumor cell proliferation and This multifaceted role of WDR4 across cancer types
survival by selectively modulating the degradation and suggests that its oncogenic mechanisms may vary
maintenance of critical proteins. 12,13 Therefore, WDR4 plays depending on the specific molecular context and the
a crucial role not only through RNA modification pathways surrounding tumor microenvironment. Understanding the
but also by influencing protein stability, making it a potential precise molecular functions and signaling interactions of
therapeutic target in cancer biology. WDR4 in different types of cancer is essential to identifying
its potential as a therapeutic target and designing targeted
This dual role in RNA modification and protein stability strategies to selectively inhibit its activity in cancer cells.
enables WDR4 to regulate several tumor-promoting
processes, underscoring its potential as a therapeutic target 2. Molecular mechanisms of WDR4 in
in oncology. tumorigenesis
1.2. Relevance of WDR4 in cancer 2.1. Structural and functional aspects of WDR4
The oncogenic functions of WDR4 in multiple The oncogenic mechanisms of WDR4 in cancer are mainly
malignancies have been studied, including hepatocellular attributable to its unique structural properties, particularly
carcinoma (HCC), 14-16 lung cancer, 17-19 head and neck its WD40 repeat domains, which form a stable beta-
27
squamous cell carcinoma, adrenocortical carcinoma, propeller structure capable of binding diverse cellular
20
21
prostate adenocarcinoma, 22,23 esophageal squamous cell partners, such as METTL1. This structure enables WDR4
28
carcinoma, hepatoblastoma, and Wilms tumor, where as a scaffold protein that coordinates cellular complexes in
24
25
26
its overexpression or polymorphism has been linked to RNA modification and protein turnover pathways.
Volume 4 Issue 1 (2025) 38 doi: 10.36922/td.5830