Epigenetic regulation of COX‑2 expression by DNA hypomethylation via NF‑κB activation in ketamine‑induced ulcerative cystitis

Chuang,Shu‑Mien; Lu,Jian‑He; Lin,Kun‑Ling; Long,Cheng‑Yu; Lee,Yung‑Chin; Hsiao,Hui‑Pin; Tsai,Chia‑Chun; Wu,Wen‑Jeng; Yang,Hui‑Jun; Juan,Yung‑Shun

doi:10.3892/ijmm.2019.4252

Epigenetic regulation of COX‑2 expression by DNA hypomethylation via NF‑κB activation in ketamine‑induced ulcerative cystitis

Authors:
- Shu‑Mien Chuang
- Jian‑He Lu
- Kun‑Ling Lin
- Cheng‑Yu Long
- Yung‑Chin Lee
- Hui‑Pin Hsiao
- Chia‑Chun Tsai
- Wen‑Jeng Wu
- Hui‑Jun Yang
- Yung‑Shun Juan
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Affiliations: Translational Research Center, Cancer Center, Department of Medical Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C., Department of Urology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C., Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C., Division of Genetics, Endocrinology and Metabolism, Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, R.O.C.
Published online on: June 21, 2019 https://doi.org/10.3892/ijmm.2019.4252
Pages: 797-812
Copyright: © Chuang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study investigated the methylation of CpG sites in the cyclooxygenase (COX)‑2 promoter via nuclear factor (NF)‑κB transcriptional regulation and elucidated its effect on the COX‑2 transcriptional expression in a ketamine‑induced ulcerative cystitis (KIC) animal model. The results of the present study revealed that ketamine treatment induced NF‑κB p65 translocation to nuclei and activated COX‑2 expression and prostaglandin (PGE)2 production in bladder tissue, whereas COX‑2 inhibitor suppressed the inflammatory effect. Moreover, DNA hypomethylation of the COX‑2 promoter region located from ‑1,522 to ‑829 bp might contribute to transcriptional regulation of COX‑2 expression and induce a pro‑inflammatory response in KIC. Ketamine treatment increased the binding of NF‑κB and permissive histone H3 lysine‑4 (H3K4)m3, but caused a decrease in the repressive histone H3K27m3 and H3K36m3 on the COX‑2 promoter ranging from ‑1,522 to ‑1,331 bp as determined by a chromatin immunoprecipitation assay. Moreover, in the ketamine group, the level of Ten‑Eleven‑Translocation methylcytosine dioxygenase for demethylation as determined by reverse transcription‑quantitative PCR assay was increased in comparison with the control group, but that was not the case for the level of DNA methyltransferases for methylation. The present findings revealed that there was a hypomethylation pattern of the COX‑2 promoter in association with the level of COX‑2 transcription in KIC.

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1	Lee YL, Lin KL, Chuang SM, Lee YC, Lu MC, Wu BN, Wu WJ, Yuan SF, Ho WT and Juan YS: Elucidating mechanisms of bladder repair after hyaluronan instillation in ketamine-induced ulcerative cystitis in animal model. Am J Pathol. 187:1945–1959. 2017. View Article : Google Scholar : PubMed/NCBI
2	Shahani R, Streutker C, Dickson B and Stewart RJ: Ketamine-associated ulcerative cystitis: A new clinical entity. Urology. 69:810–812. 2007. View Article : Google Scholar : PubMed/NCBI
3	Middela S and Pearce I: Ketamine-induced vesicopathy: A literature review. Int J Clin Pract. 65:27–30. 2011. View Article : Google Scholar
4	Chuang SM, Liu KM, Li YL, Jang MY, Lee HH, Wu WJ, Chang WC, Levin RM and Juan YS: Dual involvements of cyclooxygenase and nitric oxide synthase expressions in ketamine-induced ulcerative cystitis in rat bladder. Neurourol Urodyn. 32:1137–1143. 2013. View Article : Google Scholar : PubMed/NCBI
5	Liu KM, Chuang SM, Long CY, Lee YL, Wang CC, Lu MC, Lin RJ, Lu JH, Jang MY, Wu WJ, et al: Ketamine-induced ulcerative cystitis and bladder apoptosis involve oxidative stress mediated by mitochondria and the endoplasmic reticulum. Am J Physiol Renal Physiol. 309:F318–331. 2015. View Article : Google Scholar : PubMed/NCBI
6	Juan YS, Lee YL, Long CY, Wong JH, Jang MY, Lu JH, Wu WJ, Huang YS, Chang WC and Chuang SM: Translocation of NF-κB and expression of cyclooxygenase-2 are enhanced by ketamine-induced ulcerative cystitis in rat bladder. Am J Pathol. 185:2269–2285. 2015. View Article : Google Scholar : PubMed/NCBI
7	Jhang JF, Hsu YH, Jiang YH and Kuo HC: Elevated serum IgE may be associated with development of ketamine cystitis. J Urol. 192:1249–1256. 2014. View Article : Google Scholar : PubMed/NCBI
8	Lee CL, Jiang YH and Kuo HC: Increased apoptosis and suburothelial inflammation in patients with ketamine-related cystitis: A comparison with non-ulcerative interstitial cystitis and controls. BJU Int. 112:1156–1162. 2013. View Article : Google Scholar : PubMed/NCBI
9	Jones PL and Wolffe AP: Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol. 9:339–347. 1999. View Article : Google Scholar : PubMed/NCBI
10	Jenuwein T and Allis CD: Translating the histone code. Science. 293:1074–1080. 2001. View Article : Google Scholar : PubMed/NCBI
11	Kelavkar UP, Harya NS, Hutzley J, Bacich DJ, Monzon FA, Chandran U, Dhir R and O'Keefe DS: DNA methylation paradigm shift: 15-lipoxygenase-1 upregulation in prostatic intraepithelial neoplasia and prostate cancer by atypical promoter hypermethylation. Prostaglandins Other Lipid Mediat. 82:185–197. 2007. View Article : Google Scholar
12	Curradi M, Izzo A, Badaracco G and Landsberger N: Molecular mechanisms of gene silencing mediated by DNA methylation. Mol Cell Biol. 22:3157–3173. 2002. View Article : Google Scholar : PubMed/NCBI
13	Urnov FD and Wolffe AP: Chromatin remodeling and transcriptional activation: The cast (in order of appearance). Oncogene. 20:2991–3006. 2001. View Article : Google Scholar : PubMed/NCBI
14	Dantas Machado AC, Zhou T, Rao S, Goel P, Rastogi C, Lazarovici A, Bussemaker HJ and Rohs R: Evolving insights on how cytosine methylation affects protein-DNA binding. Brief Funct Genomics. 14:61–73. 2015. View Article : Google Scholar
15	Jin B and Robertson KD: DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol. 754:3–29. 2013. View Article : Google Scholar
16	Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, Karimi M, Bengtzén S, Nahi H, Uggla B, et al: Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks. Blood. 118:5573–5582. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kouzarides T: Chromatin modifications and their function. Cell. 128:693–705. 2007. View Article : Google Scholar : PubMed/NCBI
18	Völkel P and Angrand PO: The control of histone lysine methylation in epigenetic regulation. Biochimie. 89:1–20. 2007. View Article : Google Scholar
19	Sims RJ III and Reinberg D: Histone H3 Lys 4 methylation: Caught in a bind? Genes Dev. 20:2779–2786. 2006. View Article : Google Scholar : PubMed/NCBI
20	Zhang S, Barros SP, Niculescu MD, Moretti AJ, Preisser JS and Offenbacher S: Alteration of PTGS2 promoter methylation in chronic periodontitis. J Dent Res. 89:133–137. 2010. View Article : Google Scholar : PubMed/NCBI
21	Loo WT, Jin L, Cheung MN, Wang M and Chow LW: Epigenetic change in E-cadherin and COX-2 to predict chronic periodontitis. J Transl Med. 8:1102010. View Article : Google Scholar : PubMed/NCBI
22	Pedre X, Mastronardi F, Bruck W, Lopez-Rodas G, Kuhlmann T and Casaccia P: Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. J Neurosci. 31:3435–3445. 2011. View Article : Google Scholar : PubMed/NCBI
23	Toyota M, Shen L, Ohe-Toyota M, Hamilton SR, Sinicrope FA and Issa JP: Aberrant methylation of the Cyclooxygenase 2 CpG island in colorectal tumors. Cancer Res. 60:4044–4048. 2000.PubMed/NCBI
24	Kikuchi T, Itoh F, Toyota M, Suzuki H, Yamamoto H, Fujita M, Hosokawa M and Imai K: Aberrant methylation and histone deacetylation of cyclooxygenase 2 in gastric cancer. Int J Cancer. 97:272–277. 2002. View Article : Google Scholar : PubMed/NCBI
25	Ma X, Yang Q, Wilson KT, Kundu N, Meltzer SJ and Fulton AM: Promoter methylation regulates cyclooxygenase expression in breast cancer. Breast Cancer Res. 6:R316–R321. 2004. View Article : Google Scholar : PubMed/NCBI
26	Feinberg AP and Vogelstein B: Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature. 301:89–92. 1983. View Article : Google Scholar : PubMed/NCBI
27	Jones PA and Laird PW: Cancer epigenetics comes of age. Nat Genet. 21:163–167. 1999. View Article : Google Scholar : PubMed/NCBI
28	Chell S, Kaidi A, Williams AC and Paraskeva C: Mediators of PGE2 synthesis and signalling downstream of COX-2 represent potential targets for the prevention/treatment of colorectal cancer. Biochim Biophys Acta. 1766:104–119. 2006.PubMed/NCBI
29	Zhou Y and Hu Z: Genome-wide demethylation by 5-aza-2′-deoxycytidine alters the cell fate of stem/progenitor cells. Stem Cell Rev. 11:87–95. 2015. View Article : Google Scholar :
30	Murata H, Tsuji S, Tsujii M, Sakaguchi Y, Fu HY, Kawano S and Hori M: Promoter hypermethylation silences cyclooxygenase-2 (Cox-2) and regulates growth of human hepatocellular carcinoma cells. Lab Invest. 84:1050–1059. 2004. View Article : Google Scholar : PubMed/NCBI
31	Liou JT, Chen ZY, Ho LJ, Yang SP, Chang DM, Liang CC and Lai JH: Differential effects of triptolide and tetrandrine on activation of COX-2, NF-kappaB, and AP-1 and virus production in dengue virus-infected human lung cells. Eur J Pharmacol. 589:288–298. 2008. View Article : Google Scholar : PubMed/NCBI
32	Poligone B and Baldwin AS: Positive and negative regulation of NF-kappaB by COX-2: Roles of different prostaglandins. J Biol Chem. 276:38658–38664. 2001. View Article : Google Scholar : PubMed/NCBI
33	Glinghammar B and Rafter J: Colonic luminal contents induce cyclooxygenase 2 transcription in human colon carcinoma cells. Gastroenterology. 120:401–410. 2001. View Article : Google Scholar : PubMed/NCBI
34	Hu VY, Malley S, Dattilio A, Folsom JB, Zvara P and Vizzard MA: COX-2 and prostanoid expression in micturition pathways after cyclophosphamide-induced cystitis in the rat. Am J Physiol Regul Integr Comp Physiol. 284:R574–R585. 2003. View Article : Google Scholar
35	Li LC and Dahiya R: MethPrimer: Designing primers for methylation PCRs. Bioinformatics. 18:1427–1431. 2002. View Article : Google Scholar : PubMed/NCBI
36	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
37	Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, Kitaoka S, Ishibashi R, Ishibazawa A, Miyamoto S, et al: PGE(2) -EP(2) signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB. Br J Pharmacol. 163:1237–1249. 2011. View Article : Google Scholar : PubMed/NCBI
38	Paul AG, Chandran B and Sharma-Walia N: Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: A key player in Kaposi's sarcoma-associated herpes virus associated malignancies. Transl Res. 162:77–92. 2013. View Article : Google Scholar : PubMed/NCBI
39	Rundhaug JE, Simper MS, Surh I and Fischer SM: The role of the EP receptors for prostaglandin E2 in skin and skin cancer. Cancer Metastasis Rev. 30:465–480. 2011. View Article : Google Scholar : PubMed/NCBI
40	Müller N: COX-2 inhibitors as antidepressants and antipsychotics: Clinical evidence. Curr Opin Investig Drugs. 11:31–42. 2010.PubMed/NCBI
41	Ackerman WE IV, Summerfield TL, Vandre DD, Robinson JM and Kniss DA: Nuclear factor-kappa B regulates inducible pros-taglandin E synthase expression in human amnion mesenchymal cells. Biol Reprod. 78:68–76. 2008. View Article : Google Scholar
42	Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M and Santoro MG: Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature. 403:103–108. 2000. View Article : Google Scholar : PubMed/NCBI
43	Chen H, Cai W, Chu ESH, Tang J, Wong CC, Wong SH, Sun W, Liang Q, Fang J, Sun Z and Yu J: Hepatic cyclooxygenase-2 overexpression induced spontaneous hepatocellular carcinoma formation in mice. Oncogene. 36:4415–4426. 2017. View Article : Google Scholar : PubMed/NCBI
44	Akhtar M, Cheng Y, Magno RM, Ashktorab H, Smoot DT, Meltzer SJ and Wilson KT: Promoter methylation regulates Helicobacter pylori-stimulated cyclooxygenase-2 expression in gastric epithelial cells. Cancer Res. 61:2399–2403. 2001.PubMed/NCBI
45	Clark SJ, Harrison J and Molloy PL: Sp1 binding is inhibited by (m)Cp(m)CpG methylation. Gene. 195:67–71. 1997. View Article : Google Scholar : PubMed/NCBI
46	Pabo CO and Sauer RT: Protein-DNA recognition. Annu Rev Biochem. 53:293–321. 1984. View Article : Google Scholar : PubMed/NCBI
47	Li E and Zhang Y: DNA methylation in mammals. Cold Spring Harb Perspect Biol. 6:pp. a0191332014, View Article : Google Scholar : PubMed/NCBI
48	Chuang TJ and Chen FC: DNA methylation is associated with an increased level of conservation at nondegenerate nucleotides in mammals. Mol Biol Evol. 31:387–396. 2014. View Article : Google Scholar :
49	Kass SU, Pruss D and Wolffe AP: How does DNA methylation repress transcription? Trends Genet. 13:444–449. 1997. View Article : Google Scholar
50	Bestor TH: Gene silencing. Methylation meets acetylation. Nature. 393:311–312. 1998. View Article : Google Scholar : PubMed/NCBI
51	Davies NM, Longstreth J and Jamali F: Misoprostol therapeutics revisited. Pharmacotherapy. 21:60–73. 2001. View Article : Google Scholar : PubMed/NCBI
52	Gobejishvili L, Ghare S, Khan R, Cambon A, Barker DF, Barve S, McClain C and Hill D: Misoprostol modulates cytokine expression through a cAMP pathway: Potential therapeutic implication for liver disease. Clin Immunol. 161:291–299. 2015. View Article : Google Scholar : PubMed/NCBI