NSUNs-driven dysregulation: the next frontier in targeted cancer therapy?

Epitranscriptomic modifications represent a fundamental regulatory layer in cancer biology, with RNA methylation emerging as a pivotal mechanism governing transcriptomic dynamics. Among these, 5-methylcytosine (m⁵C) RNA methylation-a ubiquitous and conserved epitranscriptomic mark-has been identified across diverse RNA species, including mRNAs, rRNAs, tRNAs, and mitochondrial RNAs. Notably, the RNA m⁵C "writers"-enzymes responsible for installing this modification onto target RNAs-have emerged as central regulators of tumorigenesis, with NSUN (NOP2/Sun RNA methyltransferase) proteins playing a particularly pivotal role. We synthesize current knowledge of the cellular localization, substrate specificity, and biological functions of m⁵C-modifying enzymes, focusing predominantly on the NSUN family in the cancer context. We first dissect the spatiotemporal regulation patterns of NSUN proteins-from their nuclear roles in pre-mRNA processing to cytoplasmic functions in mRNA decay and translation-and their conserved methyltransferase domains that dictate target RNA recognition. This review further explores the molecular mechanisms by which NSUN proteins govern tumor progression, metastasis, and therapeutic responses, emphasizing their dual roles in both initiating oncogenic programs and maintaining cancer cell plasticity. Finally, we discuss the translational implications of targeting NSUN-mediated m⁵C pathways, highlighting small-molecule inhibitors designed against NSUN substrate specificity, combinatorial strategies with conventional chemotherapy or immunotherapy, and the promise of epitranscriptomic diagnostics and prognostic based on NSUN expression signatures. By positioning NSUN proteins as integral nodes in the RNA epigenomic network, this synthesis not only deepens our understanding of cancer pathogenesis but also identifies novel epitranscriptomic targets for precision oncology.