METTL3-mediated m6A modification of ZNF384 promotes hepatocellular carcinoma progression by transcriptionally activating ACSM1.

BACKGROUND

Hepatocellular carcinoma (HCC) is a lethal disease with a high mortality rate, and its development is influenced by various molecular mechanisms. Zinc finger protein 384 (ZNF384) has been reported to be involved in the progression of several cancers; however, its role in HCC remains elusive.

METHODS

mRNA expression levels were analyzed by quantitative real-time polymerase chain reaction, while western blotting and immunohistochemistry were performed to validate protein expression. Cell proliferation, apoptosis, and metabolic activities were examined using clonogenicity, flow cytometry, and specific assay kits. A xenograft mouse model was employed to assess the impact of acyl-CoA synthetase medium-chain family member 1 (ACSM1) depletion on HCC cell malignancy in vivo. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were conducted to explore the association between ZNF384 and ACSM1.

RESULTS

We found that ACSM1 and ZNF384 were significantly upregulated in HCC tissues and cells when compared with normal liver tissues and human liver immortalized cells. Knockdown of ACSM1 inhibited HCC cell proliferation and glucose metabolism and induced cell apoptosis. Furthermore, ACSM1 depletion suppressed the malignant progression of HCC cells in vivo. Our data indicated that ZNF384 transcriptionally activated ACSM1 in HCC cells. Overexpression of ACSM1 reversed the inhibitory effect of ZNF384 depletion on HCC cell malignancy. Further, methyltransferase-like 3 (METTL3) stabilized ZNF384 mRNA through m6A methylation.

CONCLUSION

METTL3-mediated m6A modification of ZNF384 contributed to the progression of HCC by transcriptionally activating ACSM1. This finding suggests potential therapeutic targets for this devastating disease.