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Cancer Cell International
Published in: Cancer Cell International 1/2015

Open Access 01-12-2015 | Primary research

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

Authors: 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

Published in: Cancer Cell International | Issue 1/2015

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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 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.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(Suppl):245–54.CrossRefPubMed
5.
Kim M, Bae M, Na H, Yang M. Environmental toxicants–induced epigenetic alterations and their reversers. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2012;30(4):323–67.CrossRefPubMed
6.
Leu YW, Yan PS, Fan M, Jin VX, Liu JC, Curran EM, Welshons WV, Wei SH, Davuluri RV, Plass C, et al. Loss of estrogen receptor signaling triggers epigenetic silencing of downstream targets in breast cancer. Cancer Res. 2004;64(22):8184–92.CrossRefPubMed
7.
Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23(15):5293–300.PubMedCentralCrossRefPubMed
8.
Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114(4):567–72.PubMedCentralCrossRefPubMed
9.
Dolinoy DC, Weidman JR, Jirtle RL. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol. 2007;23(3):297–307.CrossRefPubMed
10.
Hilakivi-Clarke L. Maternal exposure to diethylstilbestrol during pregnancy and increased breast cancer risk in daughters. Breast Cancer Res. 2014;16(2):208.PubMedCentralCrossRefPubMed
11.
Radford EJ, Ito M, Shi H, Corish JA, Yamazawa K, Isganaitis E, Seisenberger S, Hore TA, Reik W, Erkek S, et al. In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science. 2014;345(6198):1255903.PubMedCentralCrossRefPubMed
12.
13.
Siegel EM, Riggs BM, Delmas AL, Koch A, Hakam A, Brown KD. Quantitative DNA methylation analysis of candidate genes in cervical cancer. PLoS One. 2015;10(3):e0122495.PubMedCentralCrossRefPubMed
14.
Farkas SA, Milutin-Gasperov N, Grce M, Nilsson TK. Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer. Epigenetics. 2013;8(11):1213–25.CrossRefPubMed
15.
Smith ZD, Chan MM, Humm KC, Karnik R, Mekhoubad S, Regev A, Eggan K, Meissner A. DNA methylation dynamics of the human preimplantation embryo. Nature. 2014;511(7511):611–5.PubMedCentralCrossRefPubMed
16.
Messerschmidt DM, Knowles BB, Solter D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 2014;28(8):812–28.PubMedCentralCrossRefPubMed
17.
Hsiao SH, Lee KD, Hsu CC, Tseng MJ, Jin VX, Sun WS, Hung YC, Yeh KT, Yan PS, Lai YY, et al. DNA methylation of the Trip10 promoter accelerates mesenchymal stem cell lineage determination. Biochem Biophys Res Commun. 2010;400(3):305–12.CrossRefPubMed
18.
Hsiao SH, Huang TH, Leu YW. Excavating relics of DNA methylation changes during the development of neoplasia. Semin Cancer Biol. 2009;19(3):198–208.CrossRefPubMed
19.
20.
Frigola J, Sole X, Paz MF, Moreno V, Esteller M, Capella G, Peinado MA. Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer. Hum Mol Genet. 2005;14(2):319–26.CrossRefPubMed
21.
Teng IW, Hou PC, Lee KD, Chu PY, Yeh KT, Jin VX, Tseng MJ, Tsai SJ, Chang YS, Wu CS, et al. Targeted methylation of two tumor suppressor genes is sufficient to transform mesenchymal stem cells into cancer stem/initiating cells. Cancer Res. 2011;71(13):4653–63.CrossRefPubMed
22.
Press JZ, De Luca A, Boyd N, Young S, Troussard A, Ridge Y, Kaurah P, Kalloger SE, Blood KA, Smith M, et al. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. BMC Cancer. 2008;8:17.PubMedCentralCrossRefPubMed
23.
Gifford G, Paul J, Vasey PA, Kaye SB, Brown R. The acquisition of hMLH1 methylation in plasma DNA after chemotherapy predicts poor survival for ovarian cancer patients. Clin Cancer Res. 2004;10(13):4420–6.CrossRefPubMed
24.
Lehmann U, Celikkaya G, Hasemeier B, Langer F, Kreipe H. Promoter hypermethylation of the death-associated protein kinase gene in breast cancer is associated with the invasive lobular subtype. Cancer Res. 2002;62(22):6634–8.PubMed
25.
Yamaguchi S, Asao T, Nakamura J, Ide M, Kuwano H. High frequency of DAP-kinase gene promoter methylation in colorectal cancer specimens and its identification in serum. Cancer Lett. 2003;194(1):99–105.CrossRefPubMed
26.
Tang X, Wu W, Sun SY, Wistuba II, Hong WK, Mao L. Hypermethylation of the death-associated protein kinase promoter attenuates the sensitivity to TRAIL-induced apoptosis in human non-small cell lung cancer cells. Mol Cancer Res. 2004;2(12):685–91.PubMed
27.
Kato K, Iida S, Uetake H, Takagi Y, Yamashita T, Inokuchi M, Yamada H, Kojima K, Sugihara K. Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer. Int J Cancer. 2008;122(3):603–8.CrossRefPubMed
28.
Finnberg N, El-Deiry WS. TRAIL death receptors as tumor suppressors and drug targets. Cell Cycle. 2008;7(11):1525–8.CrossRefPubMed
29.
Jeong DH, Youm MY, Kim YN, Lee KB, Sung MS, Yoon HK, Kim KT. Promoter methylation of p16, DAPK, CDH1, and TIMP-3 genes in cervical cancer: correlation with clinicopathologic characteristics. Int J Gynecol Cancer. 2006;16(3):1234–40.CrossRefPubMed
30.
Chekhun VF, Mykytenko DO, Luk’ianova N, Pohribnyi IP. [Correction of DNA methylation disorder as a possible way to modulation of malignant cells drug resistance]. Ukr Biokhim Zh (1999). 2006;78(6):5–14.
31.
Baker EK, El-Osta A. The rise of DNA methylation and the importance of chromatin on multidrug resistance in cancer. Exp Cell Res. 2003;290(2):177–94.CrossRefPubMed
32.
Chen SJ, Kuo CC, Pan HY, Tsou TC, Yeh SC, Chang JY. Mechanistic basis of a combination D-penicillamine and platinum drugs synergistically inhibits tumor growth in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo. Biochem Pharmacol. 2015;95(1):28–37.CrossRefPubMed
33.
Onda K, Suzuki R, Tanaka S, Oga H, Oka K, Hirano T. Decitabine, a DNA methyltransferase inhibitor, reduces P-glycoprotein mRNA and protein expressions and increases drug sensitivity in drug-resistant MOLT4 and Jurkat cell lines. Anticancer Res. 2012;32(10):4439–44.PubMed
34.
35.
Yan PS, Potter D, Deatherage DE, Huang TH, Lin S. Differential methylation hybridization: profiling DNA methylation with a high-density CpG island microarray. Methods Mol Biol. 2009;507:89–106.CrossRefPubMed
36.
Liu G, Liu YJ, Lian WJ, Zhao ZW, Yi T, Zhou HY. Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells. Oncol Rep. 2014;32(2):581–8.PubMed
37.
Xinxin S, Yujie S. Aberrant DNA methylation and drug resistance of tumor cells. Yi Chuan. 2014;36(5):411–9.PubMed
38.
Maeda O, Ando T, Ohmiya N, Ishiguro K, Watanabe O, Miyahara R, Hibi Y, Nagai T, Yamada K, Goto H. Alteration of gene expression and DNA methylation in drug-resistant gastric cancer. Oncol Rep. 2014;31(4):1883–90.PubMed
39.
Candelaria M, de la Cruz-Hernandez E, Taja-Chayeb L, Perez-Cardenas E, Trejo-Becerril C, Gonzalez-Fierro A, Chavez-Blanco A, Soto-Reyes E, Dominguez G, Trujillo JE, et al. DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells. PLoS One. 2012;7(3):e29181.PubMedCentralCrossRefPubMed
40.
Lin YS, Shaw AY, Wang SG, Hsu CC, Teng IW, Tseng MJ, Huang TH, Chen CS, Leu YW, Hsiao SH. Identification of novel DNA methylation inhibitors via a two-component reporter gene system. J Biomed Sci. 2011;18:3.PubMedCentralCrossRefPubMed
41.
Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103(5):1669–75.CrossRefPubMed
42.
Hsu CC, Li HP, Hung YH, Leu YW, Wu WH, Wang FS, Lee KD, Chang PJ, Wu CS, Lu YJ, et al. Targeted methylation of CMV and E1A viral promoters. Biochem Biophys Res Commun. 2010;402(2):228–34.CrossRefPubMed
43.
Yan PS, Venkataramu C, Ibrahim A, Liu JC, Shen RZ, Diaz NM, Centeno B, Weber F, Leu YW, Shapiro CL, et al. Mapping geographic zones of cancer risk with epigenetic biomarkers in normal breast tissue. Clin Cancer Res. 2006;12(22):6626–36.CrossRefPubMed
44.
Leu YW, Rahmatpanah F, Shi H, Wei SH, Liu JC, Yan PS, Huang TH. Double RNA interference of DNMT3b and DNMT1 enhances DNA demethylation and gene reactivation. Cancer Res. 2003;63(19):6110–5.PubMed
45.
46.
47.
Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28.PubMed
48.
Siegmund KD, Marjoram P, Woo YJ, Tavare S, Shibata D. Inferring clonal expansion and cancer stem cell dynamics from DNA methylation patterns in colorectal cancers. Proc Natl Acad Sci USA. 2009;106(12):4828–33.PubMedCentralCrossRefPubMed
49.
Wermann H, Stoop H, Gillis AJ, Honecker F, van Gurp RJ, Ammerpohl O, Richter J, Oosterhuis JW, Bokemeyer C, Looijenga LH. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J Pathol. 2010;221(4):433–42.PubMed
50.
Chuang JC, Warner SL, Vollmer D, Vankayalapati H, Redkar S, Bearss DJ, Qiu X, Yoo CB, Jones PA. S110, a 5-aza-2′-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010;9(5):1443–50.PubMedCentralCrossRefPubMed
51.
Leshchenko VV, Kuo PY, Shaknovich R, Yang DT, Gellen T, Petrich A, Yu Y, Remache Y, Weniger MA, Rafiq S, et al. Genomewide DNA methylation analysis reveals novel targets for drug development in mantle cell lymphoma. Blood. 2010;116(7):1025–34.PubMedCentralCrossRefPubMed
52.
Metadata
Title
Changes in DNA methylation are associated with the development of drug resistance in cervical cancer cells
Authors
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
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2015
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-015-0248-3

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