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

Abstract

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.

Identification of Glycolysis-Related lncRNAs and the Novel lncRNA WAC-AS1 Promotes Glycolysis and Tumor Progression in Hepatocellular Carcinoma

“…Total proteins were extracted utilizing SDS (Beyotime, Shanghai, China). The detailed protocols for western blotting were based on previously described methods ( 22 ). A ChemiDoc MP Imaging System (Bio-Rad) was used to detect and normalize the protein expression levels according to the housekeeping gene β‐actin.…”

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

“…Therefore, this study not only has scientific research value but also has great clinical value. The HCC cells may be resistant to molecular targeted drugs through a variety of mechanisms: (1) compensation between different signaling pathways ( 77 – 79 ); (2) epithelial–mesenchymal transition ( 80 – 82 ); (3) cancer stem cells ( 83 – 85 ); (4) PXR and other drug metabolism clearance mechanism ( 63 ); and (5) Notch pathway and other cell prosurvival and antiapoptotic mechanisms ( 38 , 86 – 88 ). This research not only expands our molecular mechanism of HCC cell resistance to molecular targeted drugs but also helps to provide new strategies for HCC treatment.…”

Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization

“…Besides, CCNB1 decreases proliferation and S-phase cell proportion and increases apoptosis, senescence, and G0/G1-phase cell proportion in cancer ( 50 ). In hepatocellular carcinoma, translation of CCNB1 could promote proliferation, metastasis, and sorafenib resistance, Conversely, methylated CCNB1 may help reduce cancer invasion ( 52 ). CDC25C is a key protein for G2/M transition and mitotic entry ( 53 ) and determines cell survival ( 54 ).…”