{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:38:00Z","timestamp":1788323880827,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T00:00:00Z","timestamp":1754179200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Bladder cancer pathogenesis is closely linked to epigenetic alterations, particularly DNA methylation and demethylation processes. Environmental carcinogens and persistent inflammatory stimuli\u2014such as recurrent urinary tract infections\u2014can induce aberrant DNA methylation, altering gene expression profiles and contributing to malignant transformation. This review synthesizes current evidence on the role of DNA methyltransferases (DNMT1, DNMT3a, DNMT3b) and the hypermethylation of key tumour suppressor genes, including A2BP1, NPTX2, SOX11, PENK, NKX6-2, DBC1, MYO3A, and CA10, in bladder cancer. It also evaluates the therapeutic application of DNA-demethylating agents such as 5-azacytidine and highlights the impact of chronic inflammation on epigenetic regulation. Promoter hypermethylation of tumour suppressor genes leads to transcriptional silencing and unchecked cell proliferation. Urine-based DNA methylation assays provide a sensitive and specific method for non-invasive early detection, with single-target approaches offering high diagnostic precision. Animal models are increasingly employed to validate these findings, allowing the study of methylation dynamics and gene\u2013environment interactions in vivo. DNA methylation represents a key epigenetic mechanism in bladder cancer, with significant diagnostic, prognostic, and therapeutic implications. Integration of human and experimental data supports the use of methylation-based biomarkers for early detection and targeted treatment, paving the way for personalized approaches in bladder cancer management.<\/jats:p>","DOI":"10.3390\/ijms26157507","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T07:45:11Z","timestamp":1754466311000},"page":"7507","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["DNA Methylation in Bladder Cancer: Diagnostic and Therapeutic Perspectives\u2014A Narrative Review"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-1251","authenticated-orcid":false,"given":"Drago\u015f","family":"Puia","sequence":"first","affiliation":[{"name":"Department of Surgery II, \u201cGrigore T Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Urology, \u201cDr. C.I. Parhon\u201d Clinical Hospital, 700503 Iasi, Romania"},{"name":"Center for Morphological and Spectroscopic Analysis of Urinary Stones\u201d Michel Daudon\u201d, 700503 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4146-9131","authenticated-orcid":false,"given":"Marius","family":"Iv\u0103nu\u021b\u0103","sequence":"additional","affiliation":[{"name":"Department of Surgery II, \u201cGrigore T Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Urology, \u201cDr. C.I. Parhon\u201d Clinical Hospital, 700503 Iasi, Romania"},{"name":"Center for Morphological and Spectroscopic Analysis of Urinary Stones\u201d Michel Daudon\u201d, 700503 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u0103t\u0103lin","family":"Pricop","sequence":"additional","affiliation":[{"name":"Department of Surgery II, \u201cGrigore T Popa\u201d University of Medicine and Pharmacy, 700115 Iasi, Romania"},{"name":"Department of Urology, \u201cDr. C.I. Parhon\u201d Clinical Hospital, 700503 Iasi, Romania"},{"name":"Center for Morphological and Spectroscopic Analysis of Urinary Stones\u201d Michel Daudon\u201d, 700503 Iasi, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Thompson, D., Lawrentschuk, N., and Bolton, D. (2023). New Approaches to Targeting Epigenetic Regulation in Bladder Cancer. Cancers, 15.","DOI":"10.3390\/cancers15061856"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1158\/1055-9965.EPI-11-0067","article-title":"Detection of bladder cancer using novel DNA methylation biomarkers in urine sediments","volume":"20","author":"Chung","year":"2011","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Jaszek, N., Bogdanowicz, A., Siwiec, J., Starownik, R., Kwa\u015bniewski, W., and Mlak, R. (2024). Epigenetic Biomarkers as a New Diagnostic Tool in Bladder Cancer-From Early Detection to Prognosis. J. Clin. Med., 13.","DOI":"10.20944\/preprints202411.0389.v1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.4161\/epi.25927","article-title":"Alterations of DNA methylome in human bladder cancer","volume":"8","author":"Besaratinia","year":"2013","journal-title":"Epigenetics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2188","DOI":"10.1038\/s41467-019-09937-w","article-title":"Chromatin Dysregulation and DNA Methylation at Transcription Start Sites Associated with Transcriptional Repression in Cancers","volume":"10","author":"Ando","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4598","DOI":"10.1093\/nar\/29.22.4598","article-title":"Altered Chromatin Structure Associated with Methylation-Induced Gene Silencing in Cancer Cells: Correlation of Accessibility, Methylation, MeCP2 Binding and Acetylation","volume":"29","author":"Nguyen","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, J., Xu, H., He, Y., Zheng, X., Lin, T., Yang, L., Tan, P., and Wei, Q. (2024). Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer. Redox Biol., 77.","DOI":"10.1016\/j.redox.2024.103407"},{"key":"ref_8","unstructured":"Singh, P., Raychaudhuri, D., Chakraborty, B., Meher, S., Tannir, A.J., Majumdar, A., Hawkins, J., Xiong, Y., Lorenzi, P., and Sharma, P. (2024). Epigenetic modulation shapes tumor immunity and therapeutic response in bladder cancer. bioRxiv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e3114","DOI":"10.1038\/cddis.2017.458","article-title":"BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy","volume":"8","author":"Pereira","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1158\/1078-0432.CCR-13-2637","article-title":"A panel of three markers hyper- and hypomethylated in urine sediments accurately predicts bladder cancer recurrence","volume":"20","author":"Su","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"673","DOI":"10.2217\/epi-2017-0156","article-title":"The diagnostic accuracy of methylation markers in urine for the detection of bladder cancer: A systematic review","volume":"10","author":"Bosschieter","year":"2018","journal-title":"Epigenomics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.molcel.2021.01.038","article-title":"DNA hypomethylating agents increase activation and cytolytic activity of CD8+ T cells","volume":"81","author":"Bell","year":"2021","journal-title":"Mol. Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s13148-021-01029-1","article-title":"Clinical evaluation of Bladder CARE, a new epigenetic test for bladder cancer detection in urine samples","volume":"13","author":"Piatti","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Koukourikis, P., Papaioannou, M., Pervana, S., and Apostolidis, A. (2024). Exploring the DNA Methylation Profile of Genes Associated with Bladder Cancer in Bladder Tissue of Patients with Neurogenic Lower Urinary Tract Dysfunction. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25115660"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Jiang, Y.H., Liu, Y.S., Wei, Y.C., Jhang, J.F., Kuo, H.C., Huang, H.H., Chan, M.W.Y., Lin, G.L., Cheng, W.C., and Lin, S.C. (2024). Hypermethylation Loci of ZNF671, IRF8, and OTX1 as Potential Urine-Based Predictive Biomarkers for Bladder Cancer. Diagnostics, 14.","DOI":"10.3390\/diagnostics14050468"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e16004","DOI":"10.1016\/j.heliyon.2023.e16004","article-title":"Epigenetic regulation of human WIF1 and DNA methylation situation of WIF1 and GSTM5 in urothelial carcinoma","volume":"9","author":"Shen","year":"2023","journal-title":"Heliyon"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, C., Xu, X., Wang, T., Yang, M., Sun, J., He, Q., Zhao, H., Xie, W., Yuan, J., and Wang, J. (2024). Clinical performance and utility of a noninvasive urine-based methylation biomarker: TWIST1\/Vimentin to detect urothelial carcinoma of the bladder. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-58586-7"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s13148-021-01073-x","article-title":"A urine-based DNA methylation assay to facilitate early detection and risk stratification of bladder cancer","volume":"13","author":"Ruan","year":"2021","journal-title":"Clin. Epigenet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1007\/s00345-024-05287-5","article-title":"Bladder cancer detection by urinary methylation markers GHSR\/MAL: A validation study","volume":"42","author":"Beijert","year":"2024","journal-title":"World J. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Ilijazi, D., Pulverer, W., Ertl, I.E., Lemberger, U., Kimura, S., Abufaraj, M., D\u2019Andrea, D., Pradere, B., Bruchbacher, A., and Graf, A. (2020). Discovery of Molecular DNA Methylation-Based Biomarkers through Genome-Wide Analysis of Response Patterns to BCG for Bladder Cancer. Cells, 9.","DOI":"10.3390\/cells9081839"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.euf.2024.05.024","article-title":"Diagnostic test accuracy of urinary DNA methylation-based biomarkers for the detection of primary and recurrent bladder cancer: A systematic review and meta-analysis","volume":"10","author":"Carvalho","year":"2024","journal-title":"Eur. Urol. Focus"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, S., Zhang, J., Zhang, Q., Liang, Y., Du, Y., and Wang, G. (2022). Identification of Prognostic Biomarkers for Bladder Cancer Based on DNA Methylation Profile. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.817086"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3604","DOI":"10.21037\/tau-21-326","article-title":"Bioinformatics analysis to screen DNA methylation-driven genes for prognosis of patients with bladder cancer","volume":"10","author":"Zhou","year":"2021","journal-title":"Transl. Androl. Urol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s10541-005-0179-z","article-title":"DNA demethylation and carcinogenesis","volume":"70","author":"Kisseljova","year":"2005","journal-title":"Biochemistry (Moscow)"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Martinez, V.G., Rubio, C., Mart\u00ednez-Fern\u00e1ndez, M., Segovia, C., L\u00f3pez-Calder\u00f3n, F., Gar\u00edn, M., Villacampa, F., and Paramio, J.M. (2019). Epigenetics of bladder cancer: Where biomarkers and therapeutic targets meet. Front. Genet., 10.","DOI":"10.3389\/fgene.2019.01125"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Koukourikis, P., Papaioannou, M., Georgopoulos, P., Tsotridou, E., Tzortzis, V., Chaldoupis, G., Chatzidimitriou, D., Giannakis, D., and Apostolidis, A. (2023). A study of DNA methylation of bladder cancer biomarkers in the urine of patients with neurogenic lower urinary tract dysfunction. Biology, 12.","DOI":"10.3390\/biology12081126"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Kim, C., Lee, H., Park, S., Jung, H., Choi, Y., Kim, Y., Seo, J., and Han, D. (2024). Unveiling bladder cancer prognostic insights by integrating patient-matched sample and CpG methylation analysis. Medicina, 60.","DOI":"10.3390\/medicina60071175"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nunes, S.P., Henrique, R., Jer\u00f3nimo, C., and Paramio, J.M. (2020). DNA Methylation as a Therapeutic Target for Bladder Cancer. Cells, 9.","DOI":"10.3390\/cells9081850"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10903","DOI":"10.2147\/OTT.S217767","article-title":"DNA Methyltransferase Inhibitors: Catalysts for Antitumour Immune Responses","volume":"12","author":"Dan","year":"2019","journal-title":"OncoTargets Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"100","DOI":"10.34172\/ddj.2022.19","article-title":"Heparanase gene hypomethylation as a potential biomarker for precision screening of bladder cancer","volume":"11","author":"Xu","year":"2022","journal-title":"Dis. Diagn."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6278","DOI":"10.1172\/JCI139597","article-title":"Urine DNA methylation assay enables early detection and recurrence monitoring for bladder cancer","volume":"130","author":"Chen","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1158\/0008-5472.CAN-22-1444","article-title":"KDM6A Loss Triggers an Epigenetic Switch That Disrupts Urothelial Differentiation and Drives Cell Proliferation in Bladder Cancer","volume":"83","author":"Qiu","year":"2023","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3217","DOI":"10.1038\/s41419-017-0024-5","article-title":"Decitabine, a DNA-demethylating agent, promotes differentiation via NOTCH1 signaling and alters immune-related pathways in muscle-invasive bladder cancer","volume":"8","author":"Ramakrishnan","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Jung, I., An, J., and Ko, M. (2023). Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy. Biomedicines, 11.","DOI":"10.3390\/biomedicines11030654"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Puia, D., Iv\u0103nu\u021b\u0103, M., and Pricop, C. (2025). Kidney Injury Molecule-1 as a Biomarker for Renal Cancer: Current Insights and Future Perspectives\u2014A Narrative Review. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26073431"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/j.eururo.2012.01.011","article-title":"Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers","volume":"61","author":"Kandimalla","year":"2012","journal-title":"Eur. Urol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.urolonc.2008.12.008","article-title":"Increase sensitivity in detecting superficial, low grade bladder cancer by combination analysis of hypermethylation of E-cadherin, p16, p14, RASSF1A genes in urine","volume":"28","author":"Lin","year":"2010","journal-title":"Urol. Oncol."},{"key":"ref_38","first-page":"8659","article-title":"Aberrant promoter methylation profile of bladder cancer and its relationship to clinicopathological features","volume":"61","author":"Maruyama","year":"2001","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Iv\u0103nu\u021b\u0103, M., Puia, D., Cimpoe\u0219u, D.C., Iv\u0103nu\u021b\u0103, A.M., B\u00eec\u0103, O.D., and Pricop, C. (2024). Longitudinal Evaluation of Renal Function in Patients with Acquired Solitary Kidney-Urological Perspectives Post-Nephrectomy. J. Clin. Med., 13.","DOI":"10.3390\/jcm13237470"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Mancini, M., Righetto, M., Zumerle, S., Montopoli, M., and Zattoni, F. (2020). The Bladder EpiCheck Test as a Non-Invasive Tool Based on the Identification of DNA Methylation in Bladder Cancer Cells in the Urine: A Review of Published Evidence. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186542"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Deng, L., Chao, H., Deng, H., Yu, Z., Zhao, R., Huang, L., Gong, Y., Zhu, Y., Wang, Q., and Li, F. (2022). A novel and sensitive DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer. BMC Cancer, 22.","DOI":"10.1186\/s12885-022-09616-y"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Laranjeira, A.B.A., Hollingshead, M.G., Nguyen, D., Kinders, R.J., Doroshow, J.H., and Yang, S.X. (2023). DNA damage, demethylation and anticancer activity of DNA methyltransferase (DNMT) inhibitors. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-32509-4"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1111\/bph.12885","article-title":"DNA demethylation and invasive cancer: Implications for therapeutics","volume":"172","author":"Cheishvili","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e43024","DOI":"10.7554\/eLife.43024","article-title":"Epigenetic regulation of mammalian Hedgehog signaling to the stroma determines the molecular subtype of bladder cancer","volume":"8","author":"Kim","year":"2019","journal-title":"eLife"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1038\/s41586-020-3034-x","article-title":"Creation of bladder assembloids mimicking tissue regeneration and cancer","volume":"588","author":"Kim","year":"2020","journal-title":"Nature"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bo\u0161kovi\u0107, M., Roje, B., Chung, F.F., Gelemanovi\u0107, A., Cahais, V., Cuenin, C., Khoueiry, R., Vilovi\u0107, K., Herceg, Z., and Terzi\u0107, J. (2022). DNA Methylome Changes of Muscle- and Neuronal-Related Processes Precede Bladder Cancer Invasiveness. Cancers, 14.","DOI":"10.3390\/cancers14030487"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S677","DOI":"10.21037\/tcr.2017.05.41","article-title":"Epigenetic regulation in bladder cancer: Development of new prognostic targets and therapeutic implications","volume":"6","author":"Lee","year":"2017","journal-title":"Transl. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1055\/s-0041-1726685","article-title":"Aberrant DNA methylation in bladder cancer among Saudi Arabia population","volume":"11","author":"Siddiqui","year":"2021","journal-title":"J. Health Allied Sci. NU"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2691","DOI":"10.1200\/JCO.23.00699","article-title":"Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association with Clinical Outcomes","volume":"42","author":"Xu","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Shivakumar, M., Lee, Y., Bang, L., Garg, T., Sohn, K.A., and Kim, D. (2017). Identification of epigenetic interactions between miRNA and DNA methylation associated with gene expression as potential prognostic markers in bladder cancer. BMC Med. Genom., 10.","DOI":"10.1186\/s12920-017-0269-y"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"387.e1","DOI":"10.1016\/j.urolonc.2015.04.014","article-title":"Multi-institutional external validation of urinary TWIST1 and NID2 methylation as a diagnostic test for bladder cancer","volume":"33","author":"Fantony","year":"2015","journal-title":"Urol. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7507\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:22:17Z","timestamp":1760034137000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/15\/7507"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,3]]},"references-count":51,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["ijms26157507"],"URL":"https:\/\/doi.org\/10.3390\/ijms26157507","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,3]]}}}