The RNA 5-methylcytosine writer NSUN5 promotes hepatocellular carcinoma cell proliferation via a ZBED3-dependent mechanism
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Nop2/Sun domain family member 5 (NSUN5), a conserved RNA 5-methylcytosine methyltransferase, is generally considered oncogenic, but its role in the development of HCC remains unknown. In this study, we discovered that NSUN5 expression was remarkably elevated in both tumor tissues of patients as well as HCC cell lines, and was also correlated with poor clinical outcomes. NSUN5 knockdown and overexpression significantly inhibited and promoted HCC cell proliferation, respectively. Additionally, combining methylated RNA immunoprecipitation sequencing (MeRIP-seq) with RIP-seq, we identified zinc finger BED domain-containing protein 3 (ZBED3) as a novel downstream target of NSUN5. We further discovered that overexpression of ZBED3 rescued the tumor-suppressing effect of NSUN5 knockdown, and simultaneously revered the inhibition of Wnt/ß-catenin signaling pathway. In conclusion, we discovered the oncogenic role of NSUN5 in the development of HCC and identified ZBED3/Wnt/ß-catenin signaling pathway as its downstream target. This study provides a new therapeutic target that can be further developed for HCC treatment. Overall design: We integrated methylated RNA immunoprecipitation sequencing (MeRIP-seq) data with transcriptomics data to reveal the m5C profiles in NSUN5-knockdown cells. Zinc finger BED domain-containing protein 3 (ZBED3) was identified as a novel target of NSUN5.