DNA methylation enzyme inhibitor RG108 suppresses the radioresistance of esophageal cancer

Ou,Yao; Zhang,Quan; Tang,Yiting; Lu,Zhonghua; Lu,Xujing; Zhou,Xifa; Liu,Changmin

doi:10.3892/or.2018.6210

DNA methylation enzyme inhibitor RG108 suppresses the radioresistance of esophageal cancer

Authors:
- Yao Ou
- Quan Zhang
- Yiting Tang
- Zhonghua Lu
- Xujing Lu
- Xifa Zhou
- Changmin Liu
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Affiliations: Department of Radiotherapy, Changzhou Tumor Hospital, Soochow University, Changzhou, Jiangsu 213001, P.R. China, Department of Radiotherapy, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China, Department of Oncology, The Affiliated Hospital of Binzhou Medical College, Binzhou, Shandong 256603, P.R. China
Published online on: January 11, 2018 https://doi.org/10.3892/or.2018.6210
Pages: 993-1002
Copyright: © Ou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Esophageal cancer (EC) is the eighth most common highly aggressive cancer worldwide. The purpose of this study was to investigate the effect of the DNA methyltransferase inhibitor RG108 on the radiosensitivity of EC cells. MTT and clonogenic assays were performed to assess the effect of RG108 on the proliferation and radiosensitivity of Eca‑109 and TE‑1 human EC cells. The cell cycle progression and alterations in apoptosis were analyzed by flow cytometry. For the in vivo analysis, the Eca‑109 cells were inoculated into nude mice to establish tumors. Tissues from xenografts were obtained to detect changes to microvessels and tumor growth by immunohistochemistry (IHC). RNA-seq was used to identify differentially expressed genes. We found that RG108 increased the radiosensitivity of EC cells. Apoptosis and G2/M-phase arrest were induced by X-ray irradiation and were significantly enhanced by RG108. In addition, growth of tumor xenografts from the Eca‑109 cells was significantly inhibited by irradiation in combination with RG108. The RNA-seq analysis revealed that, compared with radiation alone, X-ray irradiation in combination with RG108 altered the expression of 121 genes in multiple pathways, including the TGF-β signaling pathway and the Epstein-Barr virus infection pathway. In conclusion, RG108 induced radiosensitivity in EC cells both in vitro and in vivo.

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1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al: Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet. 380:2095–2128. 2012. View Article : Google Scholar : PubMed/NCBI
3	Zhang C, Chen X, Li L, Zhou Y, Wang C and Hou S: The Association between telomere length and cancer prognosis: Evidence from a meta-analysis. PLoS One. 10:e01331742015. View Article : Google Scholar : PubMed/NCBI
4	Ito S, Ohga T, Saeki H, Nakamura T, Watanabe M, Tanaka S, Kakeji Y and Maehara Y: p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis. Int J Cancer. 113:22–28. 2005. View Article : Google Scholar : PubMed/NCBI
5	Kuwano H, Kato H, Miyazaki T, Fukuchi M, Masuda N, Nakajima M, Fukai Y, Sohda M, Kimura H and Faried A: Genetic alterations in esophageal cancer. Surg Today. 35:7–18. 2005. View Article : Google Scholar : PubMed/NCBI
6	Karahoca M and Momparler RL: Pharmacokinetic and pharmacodynamic analysis of 5-aza-2′-deoxycytidine (decitabine) in the design of its dose-schedule for cancer therapy. Clin Epigenetics. 5:32013. View Article : Google Scholar : PubMed/NCBI
7	Singh V, Sharma P and Capalash N: DNA methyltransferase-1 inhibitors as epigenetic therapy for cancer. Curr Cancer Drug Targets. 13:379–399. 2013. View Article : Google Scholar : PubMed/NCBI
8	Borges S, Döppler H, Perez EA, Andorfer CA, Sun Z, Anastasiadis PZ, Thompson E, Geiger XJ and Storz P: Pharmacologic reversion of epigenetic silencing of the PRKD1 promoter blocks breast tumor cell invasion and metastasis. Breast Cancer Res. 15:R662013. View Article : Google Scholar : PubMed/NCBI
9	Karpf AR, Moore BC, Ririe TO and Jones DA: Activation of the p53 DNA damage response pathway after inhibition of DNA methyltransferase by 5-aza-2′-deoxycytidine. Mol Pharmacol. 59:751–757. 2001. View Article : Google Scholar : PubMed/NCBI
10	Eiseler T, Döppler H, Yan IK, Goodison S and Storz P: Protein kinase D1 regulates matrix metalloproteinase expression and inhibits breast cancer cell invasion. Breast Cancer Res. 11:R132009. View Article : Google Scholar : PubMed/NCBI
11	Jüttermann R, Li E and Jaenisch R: Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation. Proc Natl Acad Sci USA. 91:pp. 11797–11801. 1994; View Article : Google Scholar : PubMed/NCBI
12	Brueckner B, Garcia Boy R, Siedlecki P, Musch T, Kliem HC, Zielenkiewicz P, Suhai S, Wiessler M and Lyko F: Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases. Cancer Res. 65:6305–6311. 2005. View Article : Google Scholar : PubMed/NCBI
13	Bardenheuer W, Lehmberg K, Rattmann I, Brueckner A, Schneider A, Sorg UR, Seeber S, Moritz T and Flasshove M: Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells. Leukemia. 19:2281–2288. 2005. View Article : Google Scholar : PubMed/NCBI
14	Wang Z, Hou J, Lu L, Qi Z, Sun J, Gao W, Meng J, Wang Y, Sun H, Gu H, et al: Small ribosomal protein subunit S7 suppresses ovarian tumorigenesis through regulation of the PI3K/AKT and MAPK pathways. PLoS One. 8:e791172013. View Article : Google Scholar : PubMed/NCBI
15	Shridhar R, Almhanna K, Meredith KL, Biagioli MC, Chuong MD, Cruz A and Hoffe SE: Radiation therapy and esophageal cancer. Cancer Contr. 20:97–110. 2013. View Article : Google Scholar
16	Jones PA and Baylin SB: The epigenomics of cancer. Cell. 128:683–692. 2007. View Article : Google Scholar : PubMed/NCBI
17	Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, Sidransky D and Umbricht CB: Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 90:4011–4018. 2005. View Article : Google Scholar : PubMed/NCBI
18	Miyamoto K, Fukutomi T, Akashi-Tanaka S, Hasegawa T, Asahara T, Sugimura T and Ushijima T: Identification of 20 genes aberrantly methylated in human breast cancers. Int J Cancer. 116:407–414. 2005. View Article : Google Scholar : PubMed/NCBI
19	McKie AB, Douglas DA, Olijslagers S, Graham J, Omar MM, Heer R, Gnanapragasam VJ, Robson CN and Leung HY: Epigenetic inactivation of the human sprouty2 (hSPRY2) homologue in prostate cancer. Oncogene. 24:2166–2174. 2005. View Article : Google Scholar : PubMed/NCBI
20	An C, Choi IS, Yao JC, Worah S, Xie K, Mansfield PF, Ajani JA, Rashid A, Hamilton SR and Wu TT: Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clin Cancer Res. 11:656–663. 2005.PubMed/NCBI
21	Feinberg AP, Cui H and Ohlsson R: DNA methylation and genomic imprinting: Insights from cancer into epigenetic mechanisms. Semin Cancer Biol. 12:389–398. 2002. View Article : Google Scholar : PubMed/NCBI
22	Egger G, Liang G, Aparicio A and Jones PA: Epigenetics in human disease and prospects for epigenetic therapy. Nature. 429:457–463. 2004. View Article : Google Scholar : PubMed/NCBI
23	Abdulhaq H and Rossetti JM: The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opin Investig Drugs. 16:1967–1975. 2007. View Article : Google Scholar : PubMed/NCBI
24	Luo J, Wang W, Tang Y, Zhou D, Gao Y, Zhang Q, Zhou X, Zhu H, Xing L and Yu J: mRNA and methylation profiling of radioresistant esophageal cancer cells: The involvement of Sall2 in acquired aggressive phenotypes. J Cancer. 8:646–656. 2017. View Article : Google Scholar : PubMed/NCBI
25	Stresemann C, Brueckner B, Musch T, Stopper H and Lyko F: Functional diversity of DNA methyltransferase inhibitors in human cancer cell lines. Cancer Res. 66:2794–2800. 2006. View Article : Google Scholar : PubMed/NCBI
26	Yang H, Tian ST, Wu RY, Chen Y, Mei ZN, Wang CY and Yang GZ: Glycoborinine induces apoptosis through mitochondrial pathway in HepG2 cells. J Asian Nat Prod Res. 16:991–999. 2014. View Article : Google Scholar : PubMed/NCBI
27	Wimardhani YS, Suniarti DF, Freisleben HJ, Wanandi SI, Siregar NC and Ikeda MA: Chitosan exerts anticancer activity through induction of apoptosis and cell cycle arrest in oral cancer cells. J Oral Sci. 56:119–126. 2014. View Article : Google Scholar : PubMed/NCBI
28	Oh KJ, Barbuto S, Pitter K, Morash J, Walensky LD and Korsmeyer SJ: A membrane-targeted BID BCL-2 homology 3 peptide is sufficient for high potency activation of BAX in vitro. J Biol Chem. 281:36999–37008. 2006. View Article : Google Scholar : PubMed/NCBI
29	He J, Li J, Ye C, Zhou L, Zhu J, Wang J, Mizota A, Furusawa Y and Zhou G: Cell cycle suspension: A novel process lurking in G₂ arrest. Cell Cycle. 10:1468–1476. 2011. View Article : Google Scholar : PubMed/NCBI
30	Zheng R, Liu Y, Zhang X, Zhao P and Deng Q: miRNA-200c enhances radiosensitivity of esophageal cancer by cell cycle arrest and targeting P21. Biomed Pharmacother. 90:517–523. 2017. View Article : Google Scholar : PubMed/NCBI
31	Liu J, Shen W, Tang Y, Zhou J, Li M, Zhu W, Yang H, Wu J, Zhang S and Cao J: Proteasome inhibitor MG132 enhances the antigrowth and antimetastasis effects of radiation in human nonsmall cell lung cancer cells. Tumour Biol. 35:7531–7539. 2014. View Article : Google Scholar : PubMed/NCBI
32	Xu D, Yang F, He H, Hu J, Lv X, Ma D and Chen YY: Expression of TMEM166 protein in human normal and tumor tissues. Appl Immunohistochem Mol Morphol. 21:543–552. 2013. View Article : Google Scholar : PubMed/NCBI
33	Sun W, Ma XM, Bai JP, Zhang GQ, Zhu YJ, Ma HM, Guo H, Chen YY and Ding JB: Transmembrane protein 166 expression in esophageal squamous cell carcinoma in Xinjiang, China. Asian Pac J Cancer Prev. 13:3713–3716. 2012. View Article : Google Scholar : PubMed/NCBI