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Updated: Jun 23, 2025
Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
Published on: May 10, 2024
ALKBH4 impedes 5-FU Sensitivity through suppressing GSDME induced pyroptosis in gastric cancer
Xin Jiang1, Zhiman Zhu1, Lina Ding1
1Department of Pathology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou, 221004, China.
Abstract:
5-Fluorouracil (5-FU) is the primary treatment option for advanced gastric cancer. However, the current challenge lies in the absence of validated biomarkers to accurately predict the efficacy and sensitivity of 5-FU in individual patients. It has been confirmed that 5-FU can regulate tumor progression by promoting gasdermin E (GSDME, encoded by DFNA5) cleavage to induce pyroptosis. Lysine demethylase ALKBH4 has been shown to be upregulated in a variety of tumors to promote tumor progression. However, its role in gastric cancer is not clear. In this study, we observed a significant upregulation of ALKBH4 expression in gastric cancer tissues compared to adjacent normal tissues, indicating its potential as a predictor for the poor prognosis of gastric cancer patients. On the contrary, GSDME exhibits low expression levels in gastric cancer and demonstrates a negative correlation with poor prognosis among patients diagnosed with gastric cancer. In addition, we also found that high expression of ALKBH4 can inhibit pyroptosis and promote the proliferation of gastric cancer cells. Mechanistically, ALKBH4 inhibits GSDME activation at the transcriptional level by inhibiting H3K4me3 histone modification in the GSDME promoter region, thereby reducing the sensitivity of gastric cancer cells to 5-FU treatment. These findings provide further insight into the regulatory mechanisms of ALKBH4 in the progression of gastric cancer and underscore its potential as a prognostic marker for predicting the sensitivity of gastric cancer cells to 5-FU treatment.
Insights
Lysine demethylase ALKBH4 promotes gastric cancer progression by inhibiting pyroptosis and reducing sensitivity to 5-Fluorouracil (5-FU). ALKBH4 upregulation predicts poor prognosis, suggesting it as a biomarker for 5-FU treatment response.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Biomarkers
Background:
- 5-Fluorouracil (5-FU) is a key treatment for advanced gastric cancer, but predicting patient response remains challenging due to a lack of validated biomarkers.
- Gasdermin E (GSDME) cleavage induces pyroptosis, a cell death mechanism targeted by 5-FU, but its role in gastric cancer and response to 5-FU is not fully understood.
- Lysine demethylase ALKBH4 is implicated in various cancers, yet its specific function in gastric cancer progression and 5-FU sensitivity is unclear.
Purpose of the Study:
- To investigate the role of ALKBH4 in gastric cancer progression and its impact on sensitivity to 5-Fluorouracil (5-FU) treatment.
- To determine if ALKBH4 expression can serve as a prognostic biomarker for gastric cancer patients.
- To elucidate the molecular mechanism by which ALKBH4 influences GSDME-mediated pyroptosis and gastric cancer cell proliferation.
Main Methods:
- Comparative analysis of ALKBH4 and GSDME expression in gastric cancer tissues versus adjacent normal tissues.
- Correlation analysis between ALKBH4/GSDME expression levels and patient prognosis.
- In vitro experiments to assess the effects of ALKBH4 on gastric cancer cell proliferation, pyroptosis, and 5-FU sensitivity.
- Investigation of ALKBH4's mechanism of action on GSDME promoter activity and histone modifications (H3K4me3).
Main Results:
- ALKBH4 expression was significantly upregulated in gastric cancer tissues and correlated with poor patient prognosis.
- GSDME expression was low in gastric cancer and negatively correlated with poor prognosis.
- High ALKBH4 expression inhibited pyroptosis, promoted gastric cancer cell proliferation, and reduced sensitivity to 5-FU.
- ALKBH4 was found to suppress GSDME activation transcriptionally by inhibiting H3K4me3 modification at the GSDME promoter.
Conclusions:
- ALKBH4 acts as an oncogene in gastric cancer by inhibiting GSDME-mediated pyroptosis and promoting proliferation.
- ALKBH4 upregulation is associated with reduced sensitivity to 5-FU chemotherapy in gastric cancer.
- ALKBH4 is a potential prognostic biomarker for predicting gastric cancer patient outcomes and response to 5-FU treatment.
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