Chidamide enhances the sensitivity of gastric cancer to 5-fluorouracil chemotherapy by suppressing the HDAC3/HNF4A/TYMS axis

Abstract Gastric cancer (GC) is among the most common malignant tumors in China and leads in incidence across all cancer types. For over three decades, the standard treatment has been traditional chemotherapy, which often involves monotherapy with 5-fluorouracil (5-FU) or its combination with other drugs. Unfortunately, nearly all cases of GC eventually develop resistance to 5-FU, typically displaying a median time to progression that ranges from 0 to 8 months. Therefore, elucidating the mechanisms of acquired resistance to 5-FU in GC continues to be a critical focus of ongoing research. Various gene and protein expression analyses were conducted utilizing techniques such as RT-qPCR, Western blot, IF, and IHC staining. Cell viability and proliferation were assessed using the CCK-8 assays and colony formation assays, respectively. Interactions among HDAC3, HNF4A, and TYMS were explored using ChIP, Co-IP, and dual-luciferase reporter assays. Chidamide increased the sensitivity of GC cells to 5-FU through the downregulation of TYMS and HDAC3. Additionally, the treatment with chidamide led to increased acetylation of HNF4A at lysine 458, due to the suppression of HDAC3, which in turn decreased phosphorylation of HNF4A at serine 313. Chidamide promoted the sensitivity of GC to 5-FU by suppressing the HDAC3/HNF4A/TYMS axis. This research may provide a foundation for using chidamide to counteract resistance to 5-FU in GC.