NSUN5-CBX8 m5C axis promotes gastric tumorigenesis by activating JAK-STAT3 signaling.

Emerging evidence implicates dysregulated RNA methylation in tumorigenesis across cancers. Among RNA methyltransferases, NSUN5 exhibits the highest alteration frequency in gastric cancer (GC), yet its functional and mechanistic contributions remain largely elusive. In this study, we report that Nsun5 gene depletion significantly suppressed gastric tumorigenesis in Trp53fl/fl; KrasLSL-G12D/+; Villin-Cre model mice. Wild-type Nsun5, but not its catalytically inactive mutant Nsun5C330A/C404A, largely rescued tumor formation in Nsun5-depleted Trp53-/-; KrasG12D/+ cells. Mechanistically, NSUN5 increases chromobox 8 (CBX8) protein levels by methylating and stabilizing CBX8 mRNA. As a core component of polycomb repressive complex 1 (PRC1), increased CBX8 protein expression leads to increased inhibition of the expression of SOCS2 and ultimately activates the JAK-STAT3 signaling pathway. Furthermore, the CBX8 inhibitor SW2-110A effectively antagonized Nsun5-triggered tumor formation by Trp53-/-; KrasG12D/+ GC cells. Collectively, our findings revealed how NSUN5 drives GC and revealed a promising lead compound that inhibits GC tumorigenesis.