In this study, we combined genomic, epigenomic, and epitranscriptomic approaches to characterize the 5-methylcytosine RNA methyltransferase, NSUN5, and showed how its epigenetic silencing produces a hypomethylation event at a particular position of the 28S rRNA that depletes the overall protein synthesis, but engages glioma cells in a particular translational program for survival under conditions of cellular stress. Here, NSUN5 is linked to central nervous system cancer.