Hongyu Wang,Liyang Liang,Yanfei Wang,Xuan Zhong,Chao Zhang,Zhipeng Liu,Jinzhong Liu,Wanning Hu
WD repeat domain 4 (WDR4) has been reported to promote tumor metastasis in various cancers. However, its precise function in colorectal cancer (CRC) has not been reported yet. Herein, the expression pattern of WDR4 in CRC was determined by analyzing Gene Expression Omnibus datasets (GSE110225, GSE127069, GSE156355, and GSE184093) and GEPIA online dataset. In vitro and in vivo experiments, including CCK-8, colony formation, flow cytometry, wound healing, transwell assays, and xenograft mouse models, were used to investigate the role of WDR4 in CRC. Firstly, data from Kaplan–Meier database showed that high expression of WDR4 was associated with the poor prognosis of CRC patients. Then, upregulation of WDR4 was confirmed in clinical CRC tissues. In vitro functional experiments suggested that overexpression of WDR4 promoted cell proliferation, migration, and invasion, while knockdown of WDR4 has the opposite effects. Also, the oncogenic role of WDR4 was also verified in in vivo experiments. CO-IP-LC/MS analysis uncovered that glycogen synthase kinase 3β (GSK3β) is the central protein that binds to WDR4. Mechanistically, WDR4 activated the β-catenin pathway by promoting GSK3β phosphorylation. This study demonstrates that WDR4 promotes CRC progression through activating GSK3β/β-catenin pathway, indicating that WDR4 might be a potential therapeutic target for CRC treatment.
Summary Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N 7 -methylguanosine (m 7 G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo . Mechanistically, m 7 G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m 7 G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m 7 G tRNA modification in promoting ICC tumorigenesis and progression in vivo . Our study uncovers the important physiological function and mechanism of METTL1-mediated m 7 G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.
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