Journal Article

MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma

Wang, Ganggang, Chen, Xi, Zhang, Zhonglin, Liu, Yingyi, Ma, Weijie, Yao, Ye, Gao, Meng, Jiang, Xiang, Zhang, Hao, Xu, Kequan, Xia, Peng, Yuan, Yufeng

2021

Overview

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, there still remains a lack of effective diagnostic and therapeutic targets for this disease. Increasing evidence demonstrates that RNA modifications play an important role in the progression of HCC, but the role of the N7-methylguanosine (m7G) methylation modification in HCC has not been properly evaluated. Thus, the goal of the present study was to investigate the function and mechanism of the m7G methyltransferase WD repeat domain 4 (WDR4) in HCC as well as its clinical relevance and potential value. We first verified the high expression of WDR4 in HCC and observed that upregulated WDR4 expression increased the m7G methylation level in HCC. WDR4 promoted HCC cell proliferation by inducing the G2/M cell cycle transition and inhibiting apoptosis in addition to enhancing metastasis and sorafenib resistance through epithelial-mesenchymal transition (EMT). Furthermore, we observed that c-MYC (MYC) can activate WDR4 transcription and that WDR4 promotes CCNB1 mRNA stability and translation to enhance HCC progression. Mechanistically, we determined that WDR4 enhances CCNB1 translation by promoting the binding of EIF2A to CCNB1 mRNA. Furthermore, CCNB1 was observed to promote PI3K and AKT phosphorylation in HCC and reduce P53 protein expression by promoting P53 ubiquitination. In summary, we elucidated the MYC/WDR4/CCNB1 signalling pathway and its impact on PI3K/AKT and P53. Furthermore, the result showed that the m7G methyltransferase WDR4 is a tumour promoter in the development and progression of HCC and may act as a candidate therapeutic target in HCC treatment.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 13/2 / 13/51 / 38/47 / 38/77 / 42/89 / 631/45/500 / 631/67/1857 / 631/80/84/2336 / 64/60 / 82/29 / 82/58 / AKT protein / Animals / Antibodies / Antineoplastic Agents - pharmacology / Apoptosis / Biochemistry / Biomedical and Life Sciences / c-Myc protein / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - secondary / Cell Biology / Cell Culture / Cell cycle / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Cyclin B1 - genetics / Cyclin B1 - metabolism / Drug Resistance, Neoplasm / Epithelial-Mesenchymal Transition - drug effects / Eukaryotic Initiation Factor-2 - metabolism / Gene Expression Regulation, Neoplastic / GTP-Binding Proteins - genetics / GTP-Binding Proteins - metabolism / Hep G2 Cells / Hepatocellular carcinoma / Humans / Immunology / Inhibitor drugs / Initiation factor eIF-2 / Life Sciences / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Mesenchyme / Metastases / Metastasis / Methyltransferase / Mice / Mice, Inbred BALB C / Mice, Nude / mRNA stability / Myc protein / p53 Protein / Phosphatidylinositol 3-Kinase - metabolism / Phosphorylation / Proto-Oncogene Proteins c-akt - metabolism / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Signal Transduction / Sorafenib - pharmacology / Targeted cancer therapy / Therapeutic applications / Therapeutic targets / Transcription / Tumor Suppressor Protein p53 - metabolism / Tumors / Ubiquitination / Xenograft Model Antitumor Assays