Multi-omics analysis reveals CMTR1 upregulation in cancer and roles in ribosomal protein gene expression and tumor growth

Abstract

The mRNA cap methyltransferase CMTR1 plays a crucial role in RNA metabolism and gene expression regulation, yet its significance in cancer remains largely unexplored. Here, we present a comprehensive multi-omics analysis of CMTR1 across various human cancers, revealing its widespread upregulation and potential as a therapeutic target. Integrating transcriptomic and proteomic data from a large set of cancer samples, we demonstrate that CMTR1 is upregulated at the mRNA, protein, and phosphoprotein levels across multiple cancer types. Functional studies using CRISPR-mediated knockout and siRNA knockdown in breast cancer models show that CMTR1 depletion significantly inhibits tumor growth both in vitro and in vivo. Transcriptomic analysis reveals that CMTR1 primarily regulates ribosomal protein genes and other transcripts containing 5 Terminal Oligopyrimidine (TOP) motifs. Additionally, CMTR1 affects the expression of snoRNA host genes and snoRNAs, suggesting a broader role in RNA metabolism. Mechanistically, we propose that CMTR1s target specificity is partly determined by mRNA structure, particularly the presence of 5TOP motifs. Furthermore, we identify a novel CMTR1 inhibitor, N97911, through in silico screening and biochemical assays, which demonstrates significant anti-tumor activity in vitro. Our findings establish CMTR1 as a key player in cancer biology, regulating critical aspects of RNA metabolism and ribosome biogenesis, and highlight its potential as a therapeutic target across multiple cancer types.