Updated project metadata. RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggest that the epitranscriptome and its associated enzymes are altered in human tumors. In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in tranformed cell lines, identified the NOL1/NOP2/Sun domain family member 7 (NSUN7) as undergoing promoter CpG island hypermethylation-associated transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to found the RNA targets of this poorly characterized putative methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript instability. Most important, proteomics analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in those liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival and an immune-like signature, providing a potential attractive therapeutic niche for the current use of immune checkpoint inhibitors in hepatocellular carcinoma.