H3K27 acetylation activated‐CD109 evokes 5‐fluorouracil resistance in gastric cancer via the JNK / MAPK signaling pathway

Drug resistance is a considerable obstacle to gastric cancer (GC) treatment. The current work aimed to elucidate the functional mechanism of CD109 in 5‐fluorouracil (5‐FU) resistance in GC. In this study, we demonstrated that CD109 was extremely heightened in 5‐FU‐resistant GC cells. CD109 deficienc...

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Bibliographic Details
Published in:Environmental toxicology 2023-12, Vol.38 (12), p.2857-2866
Main Authors: Zhou, Fei, Wang, Leiming, Ge, Han, Zhang, Diancai, Wang, Weizhi
Format: Article
Language:English
Subjects:
5-Fluorouracil
Acetylation
Apoptosis
Cancer
Cell viability
Cells
Drug resistance
Gastric cancer
MAP kinase
Metastases
Pax5 protein
Signal transduction
Therapeutic targets
Up-regulation
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Summary:Drug resistance is a considerable obstacle to gastric cancer (GC) treatment. The current work aimed to elucidate the functional mechanism of CD109 in 5‐fluorouracil (5‐FU) resistance in GC. In this study, we demonstrated that CD109 was extremely heightened in 5‐FU‐resistant GC cells. CD109 deficiency lessened the IC 50 value, impaired cell viability and metastatic capability, and induced cell apoptosis after 5‐FU treatment in cells. In addition, we found that PAX5 bound p300 increased the enrichment of H3K27ac at the promoter region of the CD109 gene, which resulted in the upregulation of CD109 in GC. Moreover, we also revealed that CD109 triggered 5‐FU resistance via activating the JNK/MAPK signaling. Blockage of JNK/MAPK signaling using JNK inhibitor, SP600125, abolished CD109 upregulation‐induced changes of IC 50 values, cell viability, metastasis and apoptosis in NCI‐N87/5‐FU and SNU‐1/5‐FU cells. Importantly, CD109 silencing enhanced the therapeutic efficacy of 5‐FU, leading to reduced tumor growth in vivo. In conclusion, our results unveiled that H3K27 acetylation activated‐CD109 enhanced 5‐FU resistance of GC cells via modulating the JNK/MAPK signaling pathway, which might provide an attractive therapeutic target for GC.
ISSN:1520-4081
1522-7278
DOI:10.1002/tox.23919