RNA modifications add a crucial layer to gene expression regulation, though the roles of many RNA modification-related genes in cancer remain largely unexplored. Here we profile 76 RNA modification-associated genes across nine distinct types of modification (N-methyladenosine, 5-methylcytosine, N,2'-O-dimethyladenosine, 2'-O-dimethyladenosine, N-methylguanosine, pseudouridine, uridylation, 2'-O-methylation, N-acetylcytidine and adenosine-to-inosine editing) in four cancer types-breast, colon, liver and lung-through a comprehensive analysis of The Cancer Genome Atlas data. Our analysis identified three candidate genes with increased expression in cancer tissues, with elevated levels associated with poor survival across multiple cancer types: the 5-methylcytosine methyltransferases NSUN2 and DNMT3B and CBP20, an N-methylguanosine binding protein. Of these, CBP20 emerged as a key candidate, with its knockdown leading to reduced cancer cell viability, apoptosis induction and G1-S cell cycle arrest. RNA sequencing further confirmed the downregulation of cell-cycle-related pathways upon CBP20 depletion. Through a signature similarity search using the Library of Integrated Network-Based Cellular Signatures dataset, we identified raloxifene, purpurogallin and enoxacin as pharmacological agents that mimic the effects of CBP20 knockdown. Treatment with these agents significantly inhibited cell growth, highlighting a potential avenue for targeted cancer therapy. These findings suggest that CBP20 plays a pivotal role in RNA modification-mediated tumor progression and may represent a promising therapeutic target in cancer treatment.