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Integrative Analysis of Histone Acetylation Regulated CYP4F12 in Esophageal Cancer Development
Yanhong Chen1, Li Wang1, Yuchen Wang1
1Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Cancer Center of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China (Y.C., Y.W., Y.F., S.Z.); and Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China (L.W., W.S., Y.S., X.Z.).
Abstract:
Current therapeutic strategies for esophageal cancer (EC) patients have yielded limited improvements in survival rates. Recent research has highlighted the influence of drug metabolism enzymes on both drug response and EC development. Our study aims to identify specific drug metabolism enzymes regulated by histone acetylation and to elucidate its molecular and clinical features. CYP4F12 exhibited a notable upregulation subsequent to trichostatin A treatment as evidenced by RNA sequencing analysis conducted on the KYSE-150 cell line. The change in gene expression was associated with increased acetylation level of histone 3 K18 and K27 in the promoter. The regulation was dependent on p300. In silicon analysis of both The Cancer Genome Atlas esophageal carcinoma and GSE53624 dataset suggested a critical role of CYP4F12 in EC development, because CYP4F12 was downregulated in tumor tissues and predicted better disease-free survival. Gene ontology analysis has uncovered a robust correlation between CYP4F12 and processes related to cell migration, as well as its involvement in cytosine-mediated immune activities. Further investigation into the relationship between immune cells and CYP4F12 expression has indicated an increased level of B cell infiltration in samples with high CYP4F12 expression. CYP4F12 was also negatively correlated with the expression of inhibitory checkpoints. An accurate predictive nomogram model was established combining with clinical factors and CYP4F12 expression. In conclusion, CYP4F12 was crucial in EC development, and targeting CYP4F12 may improve the therapeutic efficacy of current treatment in EC patients. SIGNIFICANCE STATEMENT: CYP4F12 expression was downregulated in esophageal cancer (EC) patients and could be induced by trichostatin A. During EC development, CYP4F12 was linked to reduced cell migration and increased infiltration of B cells. CYP4F12 also is a biomarker as prognostic predictors and therapeutic guide in EC patients.
Insights
Histone acetylation regulates drug metabolism enzymes in esophageal cancer (EC). Downregulated CYP4F12 in EC correlates with reduced migration and increased B cell infiltration, offering a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genomics
Background:
- Current esophageal cancer (EC) treatments offer limited survival benefits.
- Drug metabolism enzymes are increasingly recognized for their role in EC development and drug response.
- Histone acetylation's influence on these enzymes in EC is an emerging area of research.
Purpose of the Study:
- To identify drug metabolism enzymes regulated by histone acetylation in EC.
- To investigate the molecular and clinical significance of these enzymes in EC development.
- To explore CYP4F12 as a potential biomarker and therapeutic target in esophageal cancer.
Main Methods:
- RNA sequencing on the KYSE-150 cell line to assess gene expression changes after trichostatin A treatment.
- Histone acetylation analysis (H3 K18 and K27) and p300 dependency assessment.
- In silico analysis of The Cancer Genome Atlas and GSE53624 datasets for CYP4F12 expression and patient survival correlation.
- Gene Ontology analysis for functional enrichment and immune cell infiltration assessment.
- Development of a predictive nomogram model incorporating clinical factors and CYP4F12 expression.
Main Results:
- CYP4F12 was upregulated by trichostatin A, linked to increased histone H3 acetylation at its promoter, dependent on p300.
- CYP4F12 was downregulated in EC tumor tissues and associated with better disease-free survival.
- CYP4F12 expression correlated with reduced cell migration and increased B cell infiltration.
- High CYP4F12 expression was negatively correlated with inhibitory checkpoint markers.
- A predictive nomogram combining clinical factors and CYP4F12 expression was established.
Conclusions:
- CYP4F12 plays a critical role in esophageal cancer development.
- Targeting CYP4F12 may enhance the efficacy of current EC therapies.
- CYP4F12 serves as a prognostic biomarker and potential therapeutic guide for EC patients.
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