NSUN2 as an emerging epigenetic regulator in cancer: from biomarker to therapeutic target

NOL1/NOP2/SUN domain family member 2 (NSUN2), a member of the RNA methyltransferase family responsible for catalysing 5-methylcytosine (m5 C) modifications, has been increasingly recognized as a key regulatory factor in the initiation and progression of cancer. A growing body of evidence indicates that NSUN2 is aberrantly expressed in multiple malignancies, such as hepatocellular carcinoma, breast cancer, and gastric cancer, where its overexpression is frequently associated with unfavourable clinical outcomes, increased tumour aggressiveness, and resistance to therapy. Through its m5C modification activity, NSUN2 influences RNA stability, translational efficiency, and molecular interaction networks, thereby modulating critical oncogenic signalling pathways, including Wnt/β-catenin, PI3K/AKT, and epithelial-mesenchymal transition (EMT). Moreover, NSUN2 has been shown to interact with non-coding RNAs and epigenetic regulatory factors, contributing to the remodelling of the tumour microenvironment and facilitating immune evasion. Although NSUN2 is predominantly characterized by its tumour-promoting functions, emerging studies also suggest context-specific tumour-suppressive roles, highlighting its functional complexity in cancer biology. This review aims to summarize recent advances in understanding the molecular mechanisms underlying NSUN2 function, its clinical significance, and its potential as a biomarker or therapeutic target, while also discussing the challenges in translating these findings into clinical practice. A deeper understanding of NSUN2’s diverse roles in carcinogenesis may provide novel insights into RNA epigenetics and inform the development of innovative strategies for cancer diagnosis and treatment.