As a 5-methylcytosine (m5C) methyltransferase, increased NOP2/Sun RNA methyltransferase 2 (NSUN2) has been revealed to promote the progression of non-small cell lung cancer (NSCLC) through m5C modification. Herein, this study aimed to investigate the potential molecular mechanisms underlying the high NSUN2 expression in NSCLC, and the potential downstream m5C mRNAs of NSUN2 in promoting NSCLC progression. Functional analyses were conducted using in vitro MTT, EdU, transwell, wound healing, sphere and tube formation assays, and in vivo murine model. m5C modification was determined by MeRIP assay. RIP assay determined the binding between NSUN2 and SLC7A5 mRNA. The upstream molecular mechanism of the upregulation of NSUN2 expression was explored using ChIP, Co-immunoprecipitation (Co-IP), and luciferase reporter assays. NSUN2 was highly expressed in NSCLC and predicted poor outcomes in NSCLC patients. Functionally, NSUN2 silencing suppressed cancer cell proliferation, migration, stemness properties, angiogenic ability and glutamine metabolism. Mechanistically, NSUN2 induced m5C methylation modification of SLC7A5, and stabilized SLC7A5 mRNA via a YBX1-dependent mechanism. Accordingly, SLC7A5 overexpression reversed the anticancer effects of NSUN2 on above oncogenic phenotypes. Further upstream molecular mechanism analysis showed that P300 could bind to and cooperate with transcription factor SP1 to increase NSUN2 expression by Histone H3 Lysine 27 acetylation (H3K27ac). Further in vivo analyses suggested that NSUN2 silencing suppressed ESCC growth and metastasis in vivo by regulating SLC7A5 expression. In conclusion, increased NSUN2 derived by P300/SP1 complex-mediated histone acetylation promoted the growth, metastasis and glutamine metabolism of NSCLC by stabilizing SLC7A5 mRNA via m5C modification.
Zheng et al. (2025) studied this question.