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Retinoids and EZH2 inhibitors cooperate to orchestrate anti-oncogenic effects on bladder cancer cells

Cancer Gene Therapy volume 31, pages 537–551 (2024)Cite this article

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Abstract

The highly mutated nature of bladder cancers harboring mutations in chromatin regulatory genes opposing Polycomb-mediated repression highlights the importance of targeting EZH2 in bladder cancer. Furthermore, the critical role of the retinoic acid signaling pathway in the development and homeostasis of the urothelium, and the anti-oncogenic effects of retinoids are well established. Therefore, our aim is to simultaneously target EZH2 and retinoic acid signaling in bladder cancer to potentiate the therapeutic response. Here we report that this coordinated targeting strategy stimulates an anti-oncogenic profile, as reflected by inducing a synergistic reduction in cell viability that was associated with increased apoptosis and cell cycle arrest in a cooperative and orchestrated manner. This study characterized anti-oncogenic transcriptional reprogramming centered on the transcriptional regulator CHOP by stimulating the endoplasmic reticulum stress response. We further portrayed a molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of a subset of genes involved in unfolded protein responses, reflecting the molecular mechanism underlying this co-targeting strategy. These findings highlight the importance of co-targeting the EZH2 and retinoic acid pathway in bladder cancers and encourage the design of novel treatments employing retinoids coupled with EZH2 inhibitors in bladder carcinoma.

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Fig. 1: The effects of fenretinide and GSK-126 on MIBC cell viability.
Fig. 2: Synergistic effects of fenretinide and GSK-126 on cell viability.
Fig. 3: The anti-oncogenic effects of fenretinide and GSK-126.
Fig. 4: Hierarchical clustering of differentially expressed genes.
Fig. 5: The effects of fenretinide and GSK-126 on H3K27me3 profiles.
Fig. 6: Transcription factor activities of differentially expressed genes.
Fig. 7: Role of CHOP in the anti-oncogenic efficacy of combination treatment.

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Data availability

All sequencing data generated in this study have been submitted to the NCBI Gene Expression Omnibus (GEO) under accession number GSE229015. All other data supporting the findings of this study are available from the corresponding author.

References

  1. Sanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, et al. Bladder cancer. Nat Rev Dis Prim. 2017;3:17022.

    Article  PubMed  Google Scholar 

  2. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2018;174:1033.

    Article  CAS  PubMed  Google Scholar 

  3. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507:315–22.

    Article  Google Scholar 

  4. Kamoun A, de Reyniès A, Allory Y, Sjödahl G, Robertson AG, Seiler R, et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur Urol. 2020;77:420–33.

    Article  PubMed  Google Scholar 

  5. Taber A, Christensen E, Lamy P, Nordentoft I, Prip F, Lindskrog SV, et al. Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat Commun. 2020;11:4858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Lavarone E, Barbieri CM, Pasini D. Dissecting the role of H3K27 acetylation and methylation in PRC2 mediated control of cellular identity. Nat Commun. 2019;10:1679.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Piunti A, Shilatifard A. The roles of Polycomb repressive complexes in mammalian development and cancer. Nat Rev Mol Cell Biol. 2021;22:326–45.

    Article  CAS  PubMed  Google Scholar 

  8. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, et al. Molecular biology: Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science (80-). 2005;310:306–10.

    Article  CAS  Google Scholar 

  9. Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat Res Mol Mech Mutagen. 2008;647:21–9.

    Article  CAS  Google Scholar 

  10. Ren G, Baritaki S, Marathe H, Feng J, Park S, Beach S, et al. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 2012;72:3091–104.

    Article  CAS  PubMed  Google Scholar 

  11. Zhao L, Yu Y, Wu J, Bai J, Zhao Y, Li C, et al. Role of EZH2 in oral squamous cell carcinoma carcinogenesis. Gene. 2014;537:197–202.

    Article  CAS  PubMed  Google Scholar 

  12. Martínez-Fernández M, Rubio C, Segovia C, López-Calderón FF, Dueñas M, Paramio JM. EZH2 in Bladder Cancer, a Promising Therapeutic Target. Int J Mol Sci. 2015;16:27107–32.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bachmann IM, Halvorsen OJ, Collett K, Stefansson IM, Straume O, Haukaas SA, et al. EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol. 2006;24:268–73.

    Article  CAS  PubMed  Google Scholar 

  14. Bracken AP, Pasini D, Capra M, Prosperini E, Colli E, Helin K. EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003;22:5323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ezhkova E, Pasolli HA, Parker JS, Stokes N, Su IH, Hannon G, et al. Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell. 2009;136:1122–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim KH, Roberts CWM. Targeting EZH2 in cancer. Nat Med. 2016;22:128–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chen Z, Du Y, Liu X, Chen H, Weng X, Guo J, et al. EZH2 inhibition suppresses bladder cancer cell growth and metastasis via the JAK2/STAT3 signaling pathway. Oncol Lett. 2019;18:907–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhou X, Liu N, Zhang J, Ji H, Liu Y, Yang J, et al. Increased expression of EZH2 indicates aggressive potential of urothelial carcinoma of the bladder in a Chinese population. Sci Rep. 2018;8:17792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu D, Li Y, Luo G, Xiao X, Tao D, Wu X, et al. LncRNA SPRY4-IT1 sponges miR-101-3p to promote proliferation and metastasis of bladder cancer cells through up-regulating EZH2. Cancer Lett. 2017;388:281–91.

    Article  CAS  PubMed  Google Scholar 

  20. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16:241–63.

    Article  CAS  PubMed  Google Scholar 

  21. McCabe MT, Ott HM, Ganji G, Korenchuk S, Thompson C, Van Aller GS, et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature. 2012;492:108–12.

    Article  CAS  PubMed  Google Scholar 

  22. Ihira K, Dong P, Xiong Y, Watari H, Konno Y, Hanley SJB, et al. EZH2 inhibition suppresses endometrial cancer progression via miR-361/Twist axis. Oncotarget. 2017;8:13509–20.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bownes LV, Williams AP, Marayati R, Stafman LL, Markert H, Quinn CH, et al. EZH2 inhibition decreases neuroblastoma proliferation and in vivo tumor growth. PLoS One. 2021;16:e0246244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Tan J, Yang X, Zhuang L, Jiang X, Chen W, Lee PL, et al. Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev. 2007;21:1050–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise. Nat Rev Clin Oncol. 2020;17:91–107.

    Article  CAS  PubMed  Google Scholar 

  26. Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226:322–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181–93.

    Article  CAS  PubMed  Google Scholar 

  28. Chen S, Hu Q, Tao X, Xia J, Wu T, Cheng B, et al. Retinoids in cancer chemoprevention and therapy: Meta-analysis of randomized controlled trials. Front Genet. 2022;13:1–14.

    Article  Google Scholar 

  29. Clifford JL, Sabichi AL, Zou C, Yang X, Steele VE, Kelloff GJ, et al. Effects of novel phenylretinamides on cell growth and apoptosis in bladder cancer. Cancer Epidemiol Biomark Prev a Publ Am Assoc Cancer Res cosponsored Am Soc Prev Oncol 2001;10:391–5.

    CAS  Google Scholar 

  30. le Maire A, Teyssier C, Balaguer P, Bourguet W, Germain P. Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations. Cells. 2019;8:1392.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Gillespie RF, Gudas LJ. Retinoid regulated association of transcriptional co-regulators and the polycomb group protein SUZ12 with the retinoic acid response elements of Hoxa1, RARbeta(2), and Cyp26A1 in F9 embryonal carcinoma cells. J Mol Biol. 2007;372:298–316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tang XH, Gudas LJ. Retinoids, retinoic acid receptors, and cancer. Annu Rev Pathol. 2011;6:345–64.

    Article  CAS  PubMed  Google Scholar 

  33. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2001;25:402–8.

    Article  CAS  PubMed  Google Scholar 

  34. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30:2114–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liao Y, Smyth GK, Shi W. The R package Rsubread is easier, faster, cheaper and better for alignment and quantification of RNA sequencing reads. Nucleic Acids Res. 2019;47:e47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  38. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  39. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shechter D, Dormann HL, Allis CD, Hake SB. Extraction, purification and analysis of histones. Nat Protoc. 2007;2:1445–57.

    Article  CAS  PubMed  Google Scholar 

  41. Liu T, Ortiz JA, Taing L, Meyer CA, Lee B, Zhang Y, et al. Cistrome: an integrative platform for transcriptional regulation studies. Genome Biol. 2011;12:R83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based Analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Wang H, Albadine R, Magheli A, Guzzo TJ, Ball MW, Hinz S, et al. Increased EZH2 protein expression is associated with invasive urothelial carcinoma of the bladder. Urol Oncol. 2012;30:428–33.

    Article  PubMed  Google Scholar 

  44. Pawlyn C, Bright MD, Buros AF, Stein CK, Walters Z, Aronson LI, et al. Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control. Blood Cancer J. 2017;7:e549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci USA. 2003;100:11606–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yadav B, Wennerberg K, Aittokallio T, Tang J. Searching for drug synergy in complex dose-response landscapes using an interaction potency model. Comput Struct Biotechnol J. 2015;13:504–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zheng S, Wang W, Aldahdooh J, Malyutina A, Shadbahr T, Tanoli Z, et al. SynergyFinder Plus: toward better interpretation and annotation of drug combination screening datasets. Genomics Proteom Bioinforma. 2022;20:587–96.

    Article  Google Scholar 

  48. Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, et al. Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol. 2004;165:347–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kleinsimon S, Longmuss E, Rolff J, Jäger S, Eggert A, Delebinski C, et al. GADD45A and CDKN1A are involved in apoptosis and cell cycle modulatory effects of viscumTT with further inactivation of the STAT3 pathway. Sci Rep. 2018;8:5750.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Borges KS, Arboleda VA, Vilain E. Mutations in the PCNA-binding site of CDKN1C inhibit cell proliferation by impairing the entry into S phase. Cell Div. 2015;10:2.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Tiffen JC, Gunatilake D, Gallagher SJ, Gowrishankar K, Heinemann A, Cullinane C, et al. Targeting activating mutations of EZH2 leads to potent cell growth inhibition in human melanoma by derepression of tumor suppressor genes. Oncotarget. 2015;6:27023–36.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Kent LN, Leone G. The broken cycle: E2F dysfunction in cancer. Nat Rev Cancer. 2019;19:326–38.

    Article  CAS  PubMed  Google Scholar 

  53. Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8:352.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11:381–9.

    Article  CAS  PubMed  Google Scholar 

  55. Zahid MDK, Rogowski M, Ponce C, Choudhury M, Moustaid-Moussa N, Rahman SM. CCAAT/enhancer-binding protein beta (C/EBPβ) knockdown reduces inflammation, ER stress, and apoptosis, and promotes autophagy in oxLDL-treated RAW264.7 macrophage cells. Mol Cell Biochem. 2020;463:211–23.

    Article  PubMed  Google Scholar 

  56. Tolomeo M, Grimaudo S. The “Janus” Role of C/EBPs family members in cancer progression. Int J Mol Sci. 2020;21:4308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Grobet-Jeandin E, Pinar U, Parra J, Rouprêt M, Seisen T. Health-related quality of life after curative treatment for muscle-invasive bladder cancer. Nat Rev Urol. 2023;20:279–93.

    Article  PubMed  Google Scholar 

  58. Villa R, Pasini D, Gutierrez A, Morey L, Occhionorelli M, Viré E, et al. Role of the polycomb repressive complex 2 in acute promyelocytic leukemia. Cancer Cell. 2007;11:513–25.

    Article  CAS  PubMed  Google Scholar 

  59. Benoit YD, Laursen KB, Witherspoon MS, Lipkin SM, Gudas LJ. Inhibition of PRC2 histone methyltransferase activity increases TRAIL-mediated apoptosis sensitivity in human colon cancer cells. J Cell Physiol. 2013;228:764–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hu H, Tian M, Ding C, Yu S. The C/EBP Homologous Protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 2018;9:3083.

    Article  CAS  PubMed  Google Scholar 

  61. Allagnat F, Fukaya M, Nogueira TC, Delaroche D, Welsh N, Marselli L, et al. C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells. Cell Death Differ. 2012;19:1836–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duprez E, Wagner K, Koch H, Tenen DG. C/EBPbeta: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells. EMBO J. 2003;22:5806–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Marchwicka A, Marcinkowska E. Regulation of Expression of CEBP Genes by Variably Expressed Vitamin D Receptor and Retinoic Acid Receptor α in Human Acute Myeloid Leukemia Cell Lines. Int J Mol Sci. 2018;19:1918.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Gery S, Park DJ, Vuong PT, Chih DY, Lemp N, Koeffler HP. Retinoic acid regulates C/EBP homologous protein expression (CHOP), which negatively regulates myeloid target genes. Blood. 2004;104:3911–7.

    Article  CAS  PubMed  Google Scholar 

  65. Lee SR, Roh YG, Kim SK, Lee JS, Seol SY, Lee HH, et al. Activation of EZH2 and SUZ12 Regulated by E2F1 Predicts the Disease Progression and Aggressive Characteristics of Bladder Cancer. Clin Cancer Res J Am Assoc Cancer Res. 2015;21:5391–403.

    Article  CAS  Google Scholar 

  66. Poplineau M, Platet N, Mazuel A, Hérault L, N’Guyen L, Koide S, et al. Noncanonical EZH2 drives retinoic acid resistance of variant acute promyelocytic leukemias. Blood. 2022;140:2358–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Arbuckle JH, Gardina PJ, Gordon DN, Hickman HD, Yewdell JW, Pierson TC, et al. Inhibitors of the Histone Methyltransferases EZH2/1 Induce a Potent Antiviral State and Suppress Infection by Diverse Viral Pathogens. MBio. 2017;8:e01141–17.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tiffen J, Gallagher SJ, Filipp F, Gunatilake D, Emran AA, Cullinane C, et al. EZH2 Cooperates with DNA Methylation To Downregulate Key Tumor Suppressors and IFN Gene Signatures in Melanoma. J Invest Dermatol. 2020;140:2442–54.e5.

    Article  CAS  PubMed  Google Scholar 

  69. Kemp CD, Rao M, Xi S, Inchauste S, Mani H, Fetsch P, et al. Polycomb repressor complex-2 is a novel target for mesothelioma therapy. Clin Cancer Res J Am Assoc Cancer Res. 2012;18:77–90.

    Article  CAS  Google Scholar 

  70. Gulati N, Béguelin W, Giulino-Roth L. Enhancer of zeste homolog 2 (EZH2) inhibitors. Leuk Lymphoma. 2018;59:1574–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Ramakrishnan S, Granger V, Rak M, Hu Q, Attwood K, Aquila L, et al. Inhibition of EZH2 induces NK cell-mediated differentiation and death in muscle-invasive bladder cancer. Cell Death Differ. 2019;26:2100–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Ler LD, Ghosh S, Chai X, Thike AA, Heng HL, Siew EY, et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci Transl Med. 2017;9:eaai8312.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was funded by the Scientific and Technological Research Council of Turkey (TUBITAK) and the EMBO Installation Grant (No:4148). The international collaboration was supported by the EMBO Scientific Exchange Grant (No:8981). GO is a recipient of a scholarship from the Scientific and Technological Research Council of Turkey (TUBITAK) and the Council of Higher Education (YOK) within the scope of the 2211/C National PhD Scholarship Program and PhD Scholarship. BA is a recipient of a scholarship from the Scientific and Technological Research Council of Turkey (TUBITAK) project (#120C129).

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  1. These authors contributed equally: Burcu Akman, Gülden Özden-Yılmaz.

Authors and Affiliations

  1. Izmir Biomedicine and Genome Center, Izmir, Turkey

    Gizem Ozgun, Tutku Yaras, Burcu Akman, Gülden Özden-Yılmaz, Gökhan Karakülah, Serif Senturk & Serap Erkek-Ozhan

  2. Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey

    Gizem Ozgun, Tutku Yaras, Gülden Özden-Yılmaz, Gökhan Karakülah & Serif Senturk

  3. Division of Molecular Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands

    Nick Landman & Maarten van Lohuizen

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Contributions

GO, SS, and SEO developed the concept of this study. GO performed all the experiments. GO and TY analyzed and visualized the data. GO and SEO wrote the manuscript. GO, SEO, SS, GK, and MvL contributed to the study design and data interpretation. BA contributed to apoptosis and gene expression analyses after knockdown. GO-Y visualized ChIP-seq G-Viz plots. NL contributed to the method optimization and data acquisition for drug combination experiments. GO, TY, and GK performed bioinformatical analyses. SE-O supervised this work and acquired funding. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Serap Erkek-Ozhan.

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This study was approved by the Non-Interventional Research Ethics Committee of Izmir Biomedicine and Genome Center.

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Ozgun, G., Yaras, T., Akman, B. et al. Retinoids and EZH2 inhibitors cooperate to orchestrate anti-oncogenic effects on bladder cancer cells. Cancer Gene Ther 31, 537–551 (2024). https://doi.org/10.1038/s41417-024-00725-3

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