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

Haorui Hu, Yuming Wang, Hongyan Qi, Guiling Liu, Runan Wang, Jing Shen

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Article in The Journal of biological chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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6 authors.

Haorui HuDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.

Yuming WangDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.

Hongyan QiExperimental Teaching Center of Basic Medicine, Zhejiang University School of Medicine, Hangzhou, China.

Guiling LiuDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.

Runan WangDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China.

Jing ShenDepartment of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China. Electronic address: shenjingwzy@zju.edu.cn.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Acid Anhydride HydrolasesEpigenesis, GeneticJumonji Domain-Containing Histone DemethylasesNeoplasm ProteinsProtein BiosynthesisStomach NeoplasmsAnimalsBis(5'-adenosyl)triphosphataseCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceAcid Anhydride HydrolasesBis(5'-adenosyl)triphosphataseJumonji Domain-Containing Histone DemethylasesKDM6B protein, humanNeoplasm ProteinsepigeneticsFHITgastric cancerhistone demethylaseKDM6Btranslational regulationtumor suppressor genes

Identifiers

PMID41895442

DOI10.1016/j.jbc.2026.111404

PMCPMC13125197

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.