Fragile histidine triad (FHIT) suppresses gastric cancer via translational regulation of the epigenetic modifier KDM6B

Fragile histidine triad (FHIT) is a well-known tumor suppressor frequently downregulated in gastric cancer (GC), yet its molecular mechanisms remain insufficiently understood. In this study, we reveal that FHIT expression is significantly reduced during carcinogen-induced malignant transformation of gastric epithelial cells, independent of its diadenosine triphosphate hydrolase activity. Ribosome profiling and polysome analysis demonstrate that FHIT regulates the translation of lysine-specific demethylase 6B (KDM6B), a key epigenetic modulator, without altering its transcription. KDM6B promotes expression of pro-apoptotic genes, including PUMA, NOXA, GADD45, and TP53, by demethylating H3K27me3 at their promoters. Additionally, KDM6B negatively regulates cytokine-related genes such as TNFRSF12A, TNFSF9, and TNFRSF21. Functional assays, including colony formation, micronucleus assays, and xenograft tumor growth studies, confirm that FHIT's tumor-suppressive effects are independent of its enzymatic activity but rely on translational regulation mechanisms. Our findings reveal a novel FHIT-KDM6B axis that integrates translational and epigenetic regulation to inhibit gastric cancer progression. Targeting this pathway may offer promising therapeutic strategies for early-stage GC intervention.