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DNMT1 reduces cisplatin sensitivity partially through downregulating FOXO3a in ovarian cancer cells
Chong Guo1,2, Qingqing Yu3, Fangzhou Li3
1Department of Obstetrics & Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
Abstract:
Most individuals with ovarian cancer (OC) develop cisplatin resistance while undergoing treatment. Bioinformatic analysis has linked DNA Methyltransferase 1 (DNMT1) to chemoresistance development as well as FOXO3a expression in OC patients. In vitro study results revealed cisplatin treatment could induce DNMT1 expression. Knocking down of DNMT1 could decrease the IC50 of cisplatin. Treatment with cisplatin may reduce FOXO3a expression in OC cells. While in DNMT1 knockdown OC cells, treatment with cisplatin could induce FOXO3a expression. DNMT1 might suppress FOXO3a expression by promoter methylation. FOXO3a overexpression could significantly enhance cisplatin sensitivity. Meta-analysis also revealed opposite effects on OC patients- prognosis: higher expression of DNMT1 is a risk factor for both overall survival and disease-free survival, while high FOXO3a may improve the 5-year survival rate in high-grade serous adenocarcinoma OC patients. Therefore, our results indicated DNMT1 could reduce cisplatin sensitivity in OC cells partially via regulating FOXO3a.
Insights
DNA Methyltransferase 1 (DNMT1) contributes to cisplatin resistance in ovarian cancer (OC) by suppressing FOXO3a. Reducing DNMT1 enhances chemotherapy effectiveness and improves patient prognosis in OC.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Cisplatin resistance is a major challenge in ovarian cancer (OC) treatment.
- DNA Methyltransferase 1 (DNMT1) and FOXO3a are implicated in chemoresistance in OC.
- Understanding the interplay between DNMT1, FOXO3a, and cisplatin sensitivity is crucial.
Purpose of the Study:
- To investigate the role of DNMT1 in regulating cisplatin sensitivity in ovarian cancer.
- To elucidate the relationship between DNMT1, FOXO3a expression, and chemoresistance.
- To explore the prognostic significance of DNMT1 and FOXO3a in OC patients.
Main Methods:
- Bioinformatic analysis of OC patient data.
- In vitro studies involving cisplatin treatment and DNMT1 knockdown in OC cells.
- Analysis of DNMT1's effect on FOXO3a expression and promoter methylation.
- Meta-analysis of patient survival data.
Main Results:
- Cisplatin treatment increased DNMT1 expression and decreased FOXO3a expression in OC cells.
- DNMT1 knockdown reduced cisplatin IC50 and restored cisplatin-induced FOXO3a expression.
- DNMT1 suppresses FOXO3a expression via promoter methylation.
- FOXO3a overexpression enhanced cisplatin sensitivity.
- High DNMT1 expression correlated with poor OC patient survival, while high FOXO3a correlated with improved survival.
Conclusions:
- DNMT1 reduces cisplatin sensitivity in ovarian cancer cells, partly by suppressing FOXO3a.
- Targeting DNMT1 or enhancing FOXO3a may represent therapeutic strategies to overcome cisplatin resistance in OC.
- DNMT1 and FOXO3a serve as potential prognostic biomarkers for ovarian cancer.
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