Wdr4, WD repeat domain 4, is a crucial component of the METTL1-WDR4 complex, which is the methyltransferase responsible for N7-methylguanosine (m7G) modification of G46 in the variable loop of certain tRNAs. This m7G tRNA modification is essential for the integrity and stability of a large subset of tRNAs, and it impacts processes like mRNA translation [1,2,4-8]. The complex is involved in various biological pathways, and its dysregulation is linked to tumorigenesis in multiple cancer types, as well as human developmental phenotypes such as microcephaly [1]. Mouse models, especially gene knockout (KO) of Mettl1 or Wdr4 in mouse embryonic stem cells (mESCs), have shown that this complex is required for normal mRNA translation, with ribosome occupancy changes at corresponding codons in Mettl1 knockout mESCs. These KO mESCs also display defective self-renewal and neural differentiation [3].

In head and neck squamous cell carcinoma (HNSCC), conditional knockout of Mettl1 in a transgenic mouse model revealed that the METTL1/WDR4 complex promotes HNSCC progression and metastasis. Ablation of METTL1 reduced m7G levels of 16 tRNAs, inhibiting translation of oncogenic transcripts related to the PI3K/AKT/mTOR signaling pathway [5].

In hepatocellular carcinoma (HCC), WDR4 promotes cell proliferation, metastasis, and sorafenib resistance. c-MYC activates WDR4 transcription, and WDR4 enhances CCNB1 mRNA stability and translation, which in turn promotes PI3K and AKT phosphorylation and reduces P53 protein expression [2]. In lung cancer, elevated METTL1 and WDR4 expression levels are negatively associated with patient prognosis, and impaired m7G tRNA modification upon METTL1/WDR4 depletion decreases cancer cell proliferation, colony formation, and invasion [4]. In osteosarcoma, knockdown of METTL1 or WDR4 impairs tumor progression, while overexpression promotes proliferation, migration, and invasion. METTL1/WDR4 modified tRNAs enhance translation of mRNAs with more m7G tRNA-decoded codons, facilitating osteosarcoma progression and chemoresistance to doxorubicin [6].

In conclusion, Wdr4, as part of the METTL1-WDR4 complex, is essential for m7G tRNA modification, which is crucial for mRNA translation, embryonic stem cell self-renewal and differentiation. Its dysregulation is closely associated with the development and progression of multiple cancers, including HCC, lung cancer, and osteosarcoma. Studies using KO and conditional knockout (CKO) mouse models have been instrumental in revealing these disease-related roles of Wdr4, providing potential therapeutic targets for these cancers.