N6-methyladenosine reader YTHDF3-mediated zinc finger protein 41 inhibits hepatocellular carcinoma progression by transcriptional repression of Snail

Advanced metastasis of hepatocellular carcinoma (HCC) significantly contributes to high death rates among patients. The efficiency of targeted therapies and chemotherapeutic agents shows individual variability. Therefore, there is no effective treatment for advanced HCC. Zinc finger proteins (ZFPs) are known to be crucial in various tumors, especially on HCC. In our study, we verified that ZFP41 could suppress the progression and metastasis of HCC through in vitro and in vivo experiments. During the past years, N6-methyladenine (m⁶A) regulation has also been increasingly reported in HCC. To investigate whether ZFP41 could be regulated via m⁶A methylation, our results showed that YTHDF3 bound to the mRNA of ZFP41 and degrade it. Subsequently, to further elucidate the function of ZFP41, we identified Snail, a well-known oncogenic molecule, through RNA-seq. As a canonical component in the epithelial-to-mesenchymal transition (EMT) pathway, Snail plays a pivotal role and is a critical marker for tumor invasion and metastasis. Our results showed ZFP41 could inhibit Snail and the EMT pathway through its transcriptional repression. In conclusion, our study revealed that ZFP41 is a potential prognostic element for patients with HCC, and targeting ZFP41 might be used for translational clinical applications as a promising therapeutic target.

EMT; ZFP41; hepatocellular carcinoma; m6A; transcription regulation.