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Updated: Mar 31, 2026
Continuous Fluorescence-Based Endonuclease-Coupled DNA Methylation Assay to Screen for DNA Methyltransferase Inhibitors
Published on: August 5, 2022
Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells
Chih-Cheng Chen1, Kuan-Der Lee1, Mei-Yu Pai2
1Department of Hematology and Oncology, Chang Gung Memorial Hospital, Chiayi, Chang Gung University College of Medicine, Taoyuan, Taiwan ; Chang Gung Institute of Technology, Taoyuan, Taiwan.
Background And Propose:
Changes in DNA methylation are associated with changes in somatic cell fate without the alteration of coding sequences. In addition to its use as a traceable biomarker, reversible DNA methylation could also serve as a therapeutic target. In particular, if the development of drug resistance is associated with changes in DNA methylation, then demethylation might reverse the resistance phenotype. The reversion of the drug-resistance might then be feasible if the association between abnormal DNA methylation and the development of drug-resistance could be identified.
Methods:
Methylation differences between the drug-resistance cervical cancer cell, SiHa, and its derived oxaliplatin-resistant S3 cells were detected by methylation specific microarray. The drug-resistance cells were treated with demethylation agent to see if the resistance phenotype were reversed. Targeted methylation of one of the identified locus in normal cell is expected to recapitulate the development of resistance and a two-component reporter system is adopted to monitor the increase of DNA methylation in live cells.
Results:
In this report, we identified methylation changes, both genome-wide and within individual loci, in the oxaliplatin-resistant cervical cancer cell S3 compared with its parental cell line SiHa. Treatment of S3 with a demethylation agent reversed increases in methylation and allowed the expression of methylation-silenced genes. Treatment with the demethylation agent also restored the sensitivity of S3 to cisplatin, taxol, and oxaliplatin to the same level as that of SiHa. Finally, we found that methylation of the target gene Casp8AP2 is sufficient to increase drug resistance in different cells.
Conclusions:
These results suggest that global methylation is associated with the development of drug resistance and could serve as a biomarker and therapeutic target for drug resistance in cervical cancer.
Insights
DNA methylation changes are linked to drug resistance in cervical cancer cells. Demethylation can reverse this resistance, suggesting methylation as a therapeutic target for overcoming drug resistance.
Area of Science:
- Epigenetics
- Cancer Biology
- Molecular Oncology
Background:
- DNA methylation regulates gene expression without altering DNA sequence, influencing cell fate.
- Reversible DNA methylation presents potential as a biomarker and therapeutic target.
- Identifying the link between abnormal DNA methylation and drug resistance could enable reversal of resistance phenotypes.
Purpose of the Study:
- To investigate DNA methylation changes associated with acquired oxaliplatin resistance in cervical cancer cells.
- To determine if demethylation can reverse the drug-resistant phenotype.
- To explore the potential of DNA methylation as a therapeutic target for overcoming drug resistance.
Main Methods:
- Methylation-specific microarray analysis to compare methylation patterns between drug-sensitive (SiHa) and drug-resistant (S3) cervical cancer cells.
- Treatment of resistant cells with a demethylation agent to assess reversal of resistance.
- Targeted gene methylation in normal cells to model resistance development, monitored by a reporter system.
Main Results:
- Genome-wide and locus-specific methylation changes were identified in oxaliplatin-resistant S3 cells compared to SiHa cells.
- Demethylation treatment reversed methylation increases, reactivated silenced genes, and restored sensitivity to multiple chemotherapeutics (cisplatin, taxol, oxaliplatin).
- Methylation of the Casp8AP2 gene was sufficient to confer drug resistance in different cell types.
Conclusions:
- Global DNA methylation patterns are associated with the development of drug resistance in cervical cancer.
- DNA methylation serves as a potential biomarker for drug resistance.
- Targeting DNA methylation represents a viable therapeutic strategy for overcoming drug resistance in cervical cancer.
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