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 proapoptotic genes, including PUMA, NOXA, GADD45, and TP53, by demethylating H3K27me3 at their promoters. In addition, 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. Our findings reveal a novel FHIT-KDM6B axis that integrates translational and epigenetic regulation to inhibit GC progression. Targeting this pathway may offer promising therapeutic strategies for early stage GC intervention.