Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells

Chih Cheng Chen, Kuan Der Lee, Mei Yu Pai, Pei Yi Chu, Chia Chen Hsu, Chia Chen Chiu, Li Tzong Chen, Jang Yang Chang, Shu Huei Hsiao, Yu Wei Leu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 oxaliplatinresistant 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.

Original languageEnglish
Article number98
JournalCancer Cell International
Volume15
Issue number1
DOIs
Publication statusPublished - Oct 13 2015
Externally publishedYes

Fingerprint

DNA Methylation
Drug Resistance
Uterine Cervical Neoplasms
Methylation
oxaliplatin
Biomarkers
Phenotype
Paclitaxel
Cisplatin
Genes
Genome
Cell Line
Therapeutics

Keywords

  • Cancer
  • DNA methylation
  • DRUG

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

Cite this

Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells. / Chen, Chih Cheng; Lee, Kuan Der; Pai, Mei Yu; Chu, Pei Yi; Hsu, Chia Chen; Chiu, Chia Chen; Chen, Li Tzong; Chang, Jang Yang; Hsiao, Shu Huei; Leu, Yu Wei.

In: Cancer Cell International, Vol. 15, No. 1, 98, 13.10.2015.

Research output: Contribution to journalArticle

Chen, Chih Cheng ; Lee, Kuan Der ; Pai, Mei Yu ; Chu, Pei Yi ; Hsu, Chia Chen ; Chiu, Chia Chen ; Chen, Li Tzong ; Chang, Jang Yang ; Hsiao, Shu Huei ; Leu, Yu Wei. / Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells. In: Cancer Cell International. 2015 ; Vol. 15, No. 1.
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abstract = "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 oxaliplatinresistant 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.",
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AU - Chen, Chih Cheng

AU - Lee, Kuan Der

AU - Pai, Mei Yu

AU - Chu, Pei Yi

AU - Hsu, Chia Chen

AU - Chiu, Chia Chen

AU - Chen, Li Tzong

AU - Chang, Jang Yang

AU - Hsiao, Shu Huei

AU - Leu, Yu Wei

PY - 2015/10/13

Y1 - 2015/10/13

N2 - 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 oxaliplatinresistant 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.

AB - 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 oxaliplatinresistant 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.

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