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  • Review Article
  • Published:

The urothelial gene regulatory network: understanding biology to improve bladder cancer management

Oncogene volume 43, pages 1–21 (2024)Cite this article

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Abstract

The urothelium is a stratified epithelium composed of basal cells, one or more layers of intermediate cells, and an upper layer of differentiated umbrella cells. Most bladder cancers (BLCA) are urothelial carcinomas. Loss of urothelial lineage fidelity results in altered differentiation, highlighted by the taxonomic classification into basal and luminal tumors. There is a need to better understand the urothelial transcriptional networks. To systematically identify transcription factors (TFs) relevant for urothelial identity, we defined highly expressed TFs in normal human bladder using RNA-Seq data and inferred their genomic binding using ATAC-Seq data. To focus on epithelial TFs, we analyzed RNA-Seq data from patient-derived organoids recapitulating features of basal/luminal tumors. We classified TFs as “luminal-enriched”, “basal-enriched” or “common” according to expression in organoids. We validated our classification by differential gene expression analysis in Luminal Papillary vs. Basal/Squamous tumors. Genomic analyses revealed well-known TFs associated with luminal (e.g., PPARG, GATA3, FOXA1) and basal (e.g., TP63, TFAP2) phenotypes and novel candidates to play a role in urothelial differentiation or BLCA (e.g., MECOM, TBX3). We also identified TF families (e.g., KLFs, AP1, circadian clock, sex hormone receptors) for which there is suggestive evidence of their involvement in urothelial differentiation and/or BLCA. Genomic alterations in these TFs are associated with BLCA. We uncover a TF network involved in urothelial cell identity and BLCA. We identify novel candidate TFs involved in differentiation and cancer that provide opportunities for a better understanding of the underlying biology and therapeutic intervention.

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Fig. 1: The urothelium: morphological and molecular stratification during differentiation.
Fig. 2: Established and novel candidate TF involved in urothelial differentiation and BLCA.
Fig. 3: An updated morphogenetic model of BLCA progression.
Fig. 4: Building a BLCA TF gene regulatory network.
Fig. 5: The single-cell transcriptomic landscape of urothelial BLCA.

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References

  1. Hicks RM. The mammalian urinary bladder: an accommodating organ. Biol Rev Camb Philos Soc. 1975;50:215–46.

    CAS  PubMed  Google Scholar 

  2. Truschel ST, Clayton DR, Beckel JM, Yabes JG, Yao Y, Wolf-Johnston A, et al. Age-related endolysosome dysfunction in the rat urothelium. PLoS One. 2018;13:e0198817.

    PubMed  PubMed Central  Google Scholar 

  3. Jost SP, Potten CS. Urothelial proliferation in growing mice. Cell Tissue Kinet. 1986;19:155–60.

    CAS  PubMed  Google Scholar 

  4. Wang J, Batourina E, Schneider K, Souza S, Swayne T, Liu C, et al. Polyploid superficial cells that maintain the urothelial barrier are produced via incomplete cytokinesis and endoreplication. Cell Rep. 2019;25:464–.e4.

    Google Scholar 

  5. Hudoklin S, Jezernik K, Neumüller J, Pavelka M, Romih R. Electron tomography of fusiform vesicles and their organization in urothelial cells. PLoS One. 2012;7:e32935.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Varley CL, Garthwaite MAE, Cross W, Hinley J, Trejdosiewicz LK, Southgate J. PPARgamma-regulated tight junction development during human urothelial cytodifferentiation. J Cell Physiol. 2006;208:407–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Harnden P, Eardley I, Joyce AD, Southgate J. Cytokeratin 20 as an objective marker of urothelial dysplasia. Br J Urol. 1996;78:870–5.

    CAS  PubMed  Google Scholar 

  8. Gandhi D, Molotkov A, Batourina E, Schneider K, Dan H, Reiley M, et al. Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Dev Cell. 2013;26:469–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Papafotiou G, Paraskevopoulou V, Vasilaki E, Kanaki Z, Paschalidis N, Klinakis A. KRT14 marks a subpopulation of bladder basal cells with pivotal role in regeneration and tumorigenesis. Nat Commun. 2016;7:11914.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Colopy SA, Bjorling DE, Mulligan WA, Bushman W. A population of progenitor cells in the basal and intermediate layers of the murine bladder urothelium contributes to urothelial development and regeneration. Dev Dyn. 2014;243:988–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Jost SP. Cell cycle of normal bladder urothelium in developing and adult mice. Virchows Arch B Cell Pathol. 1989;57:27–36.

    CAS  Google Scholar 

  12. Shin K, Lee J, Guo N, Kim J, Lim A, Qu L, et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature. 2011;472:110–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hurst CD, Alder O, Platt FM, Droop A, Stead LF, Burns JE, et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell. 2017;32:701–.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder. Cancer Cell. 2017;171:540–.e25.

    CAS  Google Scholar 

  15. Wullweber A, Strick R, Lange F, Sikic D, Taubert H, Wach S, et al. Bladder tumor subtype commitment occurs in carcinoma in situ driven by key signaling pathways including ECM remodeling. Cancer Res. 2021;81:1552–66.

    CAS  PubMed  Google Scholar 

  16. Bondaruk J, Jaksik R, Wang Z, Cogdell D, Lee S, Chen Y, et al. The origin of bladder cancer from mucosal field effects. iScience. 2022;25:104551.

    PubMed  PubMed Central  Google Scholar 

  17. Majewski T, Yao H, Bondaruk J, Chung W, Lee S, Lee JG, et al. Whole-organ genomic characterization of mucosal field effects initiating bladder carcinogenesis. Cell Rep. 2019;26:2241–.e4.

    CAS  PubMed  Google Scholar 

  18. Lawson ARJ, Abascal F, Coorens THH, Hooks Y, O’Neill L, Latimer C, et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science. 2020;370:75–82.

    CAS  PubMed  Google Scholar 

  19. López-Knowles E, Hernández S, Malats N, Kogevinas M, Lloreta J, Carrato A, et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 2006;66:7401–4.

    PubMed  Google Scholar 

  20. Taylor CF, Platt FM, Hurst CD, Thygesen HH, Knowles MA. Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes. Hum Mol Genet. 2014;23:1964–74.

    CAS  PubMed  Google Scholar 

  21. Hedegaard J, Lamy P, Nordentoft I, Algaba F, Høyer S, Ulhøi BP, et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell. 2016;30:27–42.

    CAS  PubMed  Google Scholar 

  22. Hartmann A, Schlake G, Zaak D, Hungerhuber E, Hofstetter A, Hofstaedter F, et al. Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res. 2002;62:809–18.

    CAS  PubMed  Google Scholar 

  23. 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.

    PubMed  Google Scholar 

  24. Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. The human transcription factors. Cell. 2018;172:650–65.

    CAS  PubMed  Google Scholar 

  25. Lee SH, Hu W, Matulay JT, Silva MV, Owczarek TB, Kim K, et al. Tumor evolution and drug response in patient-derived organoid models of bladder. Cancer Cell. 2018;173:515–.e17.

    CAS  Google Scholar 

  26. ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature. 2012;489:57–74.

    Google Scholar 

  27. Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y, et al. Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun. 2020;11:5077.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Evans RM, Mangelsdorf DJ. Nuclear receptors, RXR, and the big bang. Cell. 2014;157:255–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high-affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995;270:12953–6.

    CAS  PubMed  Google Scholar 

  30. Mamtani R, Haynes K, Bilker WB, Vaughn DJ, Strom BL, Glanz K, et al. Association between longer therapy with thiazolidinediones and risk of bladder cancer: a cohort study. J Natl Cancer Inst. 2012;104:1411–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Varley CL, Stahlschmidt J, Lee W-C, Holder J, Diggle C, Selby PJ, et al. Role of PPARgamma and EGFR signalling in the urothelial terminal differentiation programme. J Cell Sci. 2004;117:2029–36.

    CAS  PubMed  Google Scholar 

  32. Santos CP, Lapi E, Martínez de Villarreal J, Álvaro-Espinosa L, Fernández-Barral A, Barbáchano A, et al. Urothelial organoids originating from Cd49fhigh mouse stem cells display Notch-dependent differentiation capacity. Nat Commun. 2019;10:4407.

    PubMed  PubMed Central  Google Scholar 

  33. Suzuki K, Koyanagi-Aoi M, Uehara K, Hinata N, Fujisawa M, Aoi T. Directed differentiation of human induced pluripotent stem cells into mature stratified bladder urothelium. Sci Rep. 2019;9:10506.

    PubMed  PubMed Central  Google Scholar 

  34. Weiss RM, Guo S, Shan A, Shi H, Romano R-A, Sinha S, et al. Brg1 determines urothelial cell fate during ureter development. J Am Soc Nephrol. 2013;24:618–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu C, Tate T, Batourina E, Truschel ST, Potter S, Adam M, et al. Pparg promotes differentiation and regulates mitochondrial gene expression in bladder epithelial cells. Nat Commun. 2019;10:4589.

    PubMed  PubMed Central  Google Scholar 

  36. Liang F-X, Bosland MC, Huang H, Romih R, Baptiste S, Deng F-M, et al. Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement. J Cell Biol. 2005;171:835–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Pascual G, Fong AL, Ogawa S, Gamliel A, Li AC, Perissi V, et al. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005;437:759–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Tate T, Xiang T, Wobker SE, Zhou M, Chen X, Kim H, et al. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat Commun. 2021;12:6160.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  40. Rochel N, Krucker C, Coutos-Thévenot L, Osz J, Zhang R, Guyon E, et al. Recurrent activating mutations of PPARγ associated with luminal bladder tumors. Nat Commun. 2019;10:253.

    PubMed  PubMed Central  Google Scholar 

  41. Halstead AM, Kapadia CD, Bolzenius J, Chu CE, Schriefer A, Wartman LD, et al. Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation. eLife. 2017;6:e30862.

    PubMed  PubMed Central  Google Scholar 

  42. Korpal M, Puyang X, Jeremy Wu Z, Seiler R, Furman C, Oo HZ, et al. Evasion of immunosurveillance by genomic alterations of PPARγ/RXRα in bladder cancer. Nat Commun. 2017;8:103.

    PubMed  PubMed Central  Google Scholar 

  43. Coutos-Thévenot L, Beji S, Neyret-Kahn H, Pippo Q, Fontugne J, Osz J, et al. PPARγ is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities. BioRxiv. 2019; https://doi.org/10.1101/868190.

  44. Warrick JI, Walter V, Yamashita H, Chung E, Shuman L, Amponsa VO, et al. FOXA1, GATA3 and ppar? cooperate to drive luminal subtype in bladder cancer: a molecular analysis of established human cell lines. Sci Rep. 2016;6:38531.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Tortora D, Roberts ME, Kumar G, Kotapalli SS, Ritch E, Scurll JM, et al. A genome-wide CRISPR screen maps endogenous regulators of PPARG gene expression in bladder cancer. iScience. 2023;26:106525.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Goldstein JT, Berger AC, Shih J, Duke FF, Furst L, Kwiatkowski DJ, et al. Genomic activation of PPARG reveals a candidate therapeutic axis in bladder cancer. Cancer Res. 2017;77:6987–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sanchez DJ, Missiaen R, Skuli N, Steger DJ, Simon MC. Cell-intrinsic tumorigenic functions of PPARγ in bladder urothelial carcinoma. Mol Cancer Res. 2021;19:598–611.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ko LJ, Engel JD. DNA-binding specificities of the GATA transcription factor family. Mol Cell Biol. 1993;13:4011–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. van der Ven AT, Connaughton DM, Ityel H, Mann N, Nakayama M, Chen J, et al. Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol. 2018;29:2348–61.

    PubMed  PubMed Central  Google Scholar 

  50. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006;127:1041–55.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Higgins JPT, Kaygusuz G, Wang L, Montgomery K, Mason V, Zhu SX, et al. Placental S100 (S100P) and GATA3: markers for transitional epithelium and urothelial carcinoma discovered by complementary DNA microarray. Am J Surg Pathol. 2007;31:673–80.

    PubMed  Google Scholar 

  52. Ainoya K, Moriguchi T, Ohmori S, Souma T, Takai J, Morita M, et al. UG4 enhancer-driven GATA-2 and bone morphogenetic protein 4 complementation remedies the CAKUT phenotype in Gata2 hypomorphic mutant mice. Mol Cell Biol. 2012;32:2312–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hoshino T, Shimizu R, Ohmori S, Nagano M, Pan X, Ohneda O, et al. Reduced BMP4 abundance in Gata2 hypomorphic mutant mice result in uropathies resembling human CAKUT. Genes Cells. 2008;13:159–70.

    CAS  PubMed  Google Scholar 

  54. Fishwick C, Higgins J, Percival-Alwyn L, Hustler A, Pearson J, Bastkowski S, et al. Heterarchy of transcription factors driving basal and luminal cell phenotypes in human urothelium. Cell Death Differ. 2017;24:809–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Wang C, Yang S, Jin L, Dai G, Yao Q, Xiang H, et al. Biological and clinical significance of GATA3 detected from TCGA database and FFPE sample in bladder cancer patients. Onco Targets Ther. 2020;13:945–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Iyyanki T, Zhang B, Wang Q, Hou Y, Jin Q, Xu J, et al. Subtype-associated epigenomic landscape and 3D genome structure in bladder cancer. Genome Biol. 2021;22:105.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lerner SP, McConkey DJ, Hoadley KA, Chan KS, Kim WY, Radvanyi F, et al. Bladder cancer molecular taxonomy: summary from a consensus meeting. Bladder Cancer. 2016;2:37–47.

    PubMed  PubMed Central  Google Scholar 

  58. Miyamoto H, Izumi K, Yao JL, Li Y, Yang Q, McMahon LA, et al. GATA binding protein 3 is down-regulated in bladder cancer yet strong expression is an independent predictor of poor prognosis in invasive tumor. Hum Pathol. 2012;43:2033–40.

    CAS  PubMed  Google Scholar 

  59. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Eriksson P, Aine M, Veerla S, Liedberg F, Sjödahl G, Höglund M. Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems. BMC Med Genom. 2015;8:25.

    Google Scholar 

  61. van Kessel KEM, van der Keur KA, Dyrskjøt L, Algaba F, Welvaart NYC, Beukers W, et al. Molecular markers increase precision of the European Association of Urology non-muscle-invasive bladder cancer progression risk groups. Clin Cancer Res. 2018;24:1586–93.

    PubMed  Google Scholar 

  62. Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature. 1993;364:412–20.

    CAS  PubMed  Google Scholar 

  63. Cirillo LA, McPherson CE, Bossard P, Stevens K, Cherian S, Shim EY, et al. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J. 1998;17:244–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Cirillo LA, Lin FR, Cuesta I, Friedman D, Jarnik M, Zaret KS. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol Cell. 2002;9:279–89.

    CAS  PubMed  Google Scholar 

  65. Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012;148:72–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Tsuchiya H, da Costa K-A, Lee S, Renga B, Jaeschke H, Yang Z, et al. Interactions between nuclear receptor SHP and FOXA1 maintain oscillatory homocysteine homeostasis in mice. Gastroenterology. 2015;148:1012–.e14.

    CAS  PubMed  Google Scholar 

  67. Belikov S, Astrand C, Wrange O. FoxA1 binding directs chromatin structure and the functional response of a glucocorticoid receptor-regulated promoter. Mol Cell Biol. 2009;29:5413–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Besnard V, Wert SE, Hull WM, Whitsett JA. Immunohistochemical localization of Foxa1 and Foxa2 in mouse embryos and adult tissues. Gene Expr Patterns. 2004;5:193–208.

    CAS  PubMed  Google Scholar 

  69. Oottamasathien S, Wang Y, Williams K, Franco OE, Wills ML, Thomas JC, et al. Directed differentiation of embryonic stem cells into bladder tissue. Dev Biol. 2007;304:556–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Varley CL, Bacon EJ, Holder JC, Southgate J. FOXA1 and IRF-1 intermediary transcriptional regulators of PPARgamma-induced urothelial cytodifferentiation. Cell Death Differ. 2009;16:103–14.

    CAS  PubMed  Google Scholar 

  71. DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, Yu X, et al. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS One. 2012;7:e36669.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Guo Y, Yuan X, Li K, Dai M, Zhang L, Wu Y, et al. GABPA is a master regulator of luminal identity and restrains aggressive diseases in bladder cancer. Cell Death Differ. 2020;27:1862–77.

    CAS  PubMed  Google Scholar 

  73. Reddy OL, Cates JM, Gellert LL, Crist HS, Yang Z, Yamashita H, et al. Loss of FOXA1 drives sexually dimorphic changes in urothelial differentiation and is an independent predictor of poor prognosis in bladder cancer. Am J Pathol. 2015;185:1385–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Osei-Amponsa V, Buckwalter JM, Shuman L, Zheng Z, Yamashita H, Walter V, et al. Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer. Oncogene. 2020;39:1302–17.

    CAS  PubMed  Google Scholar 

  75. Bernardo GM, Keri RA. FOXA1: a transcription factor with parallel functions in development and cancer. Biosci Rep. 2012;32:113–30.

    CAS  PubMed  Google Scholar 

  76. Robinson D, Van Allen EM, Wu Y-M, Schultz N, Lonigro RJ, Mosquera J-M, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, et al. Comprehensive molecular portraits of invasive lobular breast cancer. Cell. 2015;163:506–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Sikic D, Eckstein M, Wirtz RM, Jarczyk J, Worst TS, Porubsky S, et al. FOXA1 gene expression for defining molecular subtypes of muscle-invasive bladder cancer after radical cystectomy. J Clin Med. 2020;9:994.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Oettgen P, Alani RM, Barcinski MA, Brown L, Akbarali Y, Boltax J, et al. Isolation and characterization of a novel epithelium-specific transcription factor, ESE-1, a member of the ets family. Mol Cell Biol. 1997;17:4419–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Ng AY-N, Waring P, Ristevski S, Wang C, Wilson T, Pritchard M, et al. Inactivation of the transcription factor Elf3 in mice results in dysmorphogenesis and altered differentiation of intestinal epithelium. Gastroenterology. 2002;122:1455–66.

    CAS  PubMed  Google Scholar 

  81. Böck M, Hinley J, Schmitt C, Wahlicht T, Kramer S, Southgate J. Identification of ELF3 as an early transcriptional regulator of human urothelium. Dev Biol. 2014;386:321–30.

    PubMed  Google Scholar 

  82. Na L, Wang Z, Bai Y, Sun Y, Dong D, Wang W, et al. WNT7B represses epithelial-mesenchymal transition and stem-like properties in bladder urothelial carcinoma. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166271.

    CAS  PubMed  Google Scholar 

  83. Gondkar K, Patel K, Krishnappa S, Patil A, Nair B, Sundaram GM, et al. E74 like ETS transcription factor 3 (ELF3) is a negative regulator of epithelial- mesenchymal transition in bladder carcinoma. Cancer Biomark. 2019;25:223–32.

    CAS  PubMed  Google Scholar 

  84. Ting SB, Wilanowski T, Cerruti L, Zhao L-L, Cunningham JM, Jane SM. The identification and characterization of human Sister-of-Mammalian Grainyhead (SOM) expands the grainyhead-like family of developmental transcription factors. Biochem J. 2003;370:953–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Traylor-Knowles N, Hansen U, Dubuc TQ, Martindale MQ, Kaufman L, Finnerty JR. The evolutionary diversification of LSF and Grainyhead transcription factors preceded the radiation of basal animal lineages. BMC Evol Biol. 2010;10:101.

    PubMed  PubMed Central  Google Scholar 

  86. Yu Z, Mannik J, Soto A, Lin KK, Andersen B. The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation. EMBO J. 2009;28:1890–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Osborn SL, Thangappan R, Luria A, Lee JH, Nolta J, Kurzrock EA. Induction of human embryonic and induced pluripotent stem cells into urothelium. Stem Cells Transl Med. 2014;3:610–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wezel F, Lustig J, Azoitei A, Liu J, Meessen S, Najjar G, et al. Grainyhead-like 3 influences migration and invasion of urothelial carcinoma cells. Int J Mol Sci. 2021;22:2959.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ghioni P, Bolognese F, Duijf PHG, Van Bokhoven H, Mantovani R, Guerrini L. Complex transcriptional effects of p63 isoforms: identification of novel activation and repression domains. Mol Cell Biol. 2002;22:8659–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Augustin M, Bamberger C, Paul D, Schmale H. Cloning and chromosomal mapping of the human p53-related KET gene to chromosome 3q27 and its murine homolog Ket to mouse chromosome 16. Mamm Genome. 1998;9:899–902.

    CAS  PubMed  Google Scholar 

  91. Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, et al. Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nat Med. 1998;4:839–43.

    CAS  PubMed  Google Scholar 

  92. Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, et al. p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell. 1998;2:305–16.

    CAS  PubMed  Google Scholar 

  93. Dohn M, Zhang S, Chen X. p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes. Oncogene. 2001;20:3193–205.

    CAS  PubMed  Google Scholar 

  94. Lohrum MA, Vousden KH. Regulation and function of the p53-related proteins: same family, different rules. Trends Cell Biol. 2000;10:197–202.

    CAS  PubMed  Google Scholar 

  95. Koster MI, Kim S, Mills AA, DeMayo FJ, Roop DR. p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 2004;18:126–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Guo X, Keyes WM, Papazoglu C, Zuber J, Li W, Lowe SW, et al. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nat Cell Biol. 2009;11:1451–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Helton ES, Zhu J, Chen X. The unique NH2-terminally deleted (DeltaN) residues, the PXXP motif, and the PPXY motif are required for the transcriptional activity of the DeltaN variant of p63. J Biol Chem. 2006;281:2533–42.

    CAS  PubMed  Google Scholar 

  98. Kouwenhoven EN, Oti M, Niehues H, van Heeringen SJ, Schalkwijk J, Stunnenberg HG, et al. Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation. EMBO Rep. 2015;16:863–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Somerville TDD, Xu Y, Miyabayashi K, Tiriac H, Cleary CR, Maia-Silva D, et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep. 2018;25:1741–.e7.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Yang A, McKeon F. P63 and P73: P53 mimics, menaces and more. Nat Rev Mol Cell Biol. 2000;1:199–207.

    CAS  PubMed  Google Scholar 

  101. Karni-Schmidt O, Castillo-Martin M, Shen TH, Gladoun N, Domingo-Domenech J, Sanchez-Carbayo M, et al. Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression. Am J Pathol. 2011;178:1350–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398:708–13.

    CAS  PubMed  Google Scholar 

  103. Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature. 1999;398:714–8.

    CAS  PubMed  Google Scholar 

  104. Paris M, Rouleau M, Pucéat M, Aberdam D. Regulation of skin aging and heart development by TAp63. Cell Death Differ. 2012;19:186–93.

    CAS  PubMed  Google Scholar 

  105. Urist MJ, Di Como CJ, Lu M-L, Charytonowicz E, Verbel D, Crum CP, et al. Loss of p63 expression is associated with tumor progression in bladder cancer. Am J Pathol. 2002;161:1199–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Signoretti S, Pires MM, Lindauer M, Horner JW, Grisanzio C, Dhar S, et al. p63 regulates commitment to the prostate cell lineage. Proc Natl Acad Sci USA. 2005;102:11355–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Cheng W, Jacobs WB, Zhang JJR, Moro A, Park J-H, Kushida M, et al. DeltaNp63 plays an anti-apoptotic role in ventral bladder development. Development. 2006;133:4783–92.

    CAS  PubMed  Google Scholar 

  108. Celli J, Duijf P, Hamel BC, Bamshad M, Kramer B, Smits AP, et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell. 1999;99:143–53.

    CAS  PubMed  Google Scholar 

  109. van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, et al. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation. Am J Hum Genet. 2001;69:481–92.

    PubMed  PubMed Central  Google Scholar 

  110. Duijf PHG, Vanmolkot KRJ, Propping P, Friedl W, Krieger E, McKeon F, et al. Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63. Hum Mol Genet. 2002;11:799–804.

    CAS  PubMed  Google Scholar 

  111. McGrath JA, Duijf PH, Doetsch V, Irvine AD, de Waal R, Vanmolkot KR, et al. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63. Hum Mol Genet. 2001;10:221–9.

    CAS  PubMed  Google Scholar 

  112. Kloesch B, Ionasz V, Paliwal S, Hruschka N, Martinez de Villarreal J, Öllinger R, et al. A GATA6-centred gene regulatory network involving HNFs and ΔNp63 controls plasticity and immune escape in pancreatic cancer. Gut. 2022;71:766–77.

    CAS  PubMed  Google Scholar 

  113. Bankhead A, McMaster T, Wang Y, Boonstra PS, Palmbos PL. TP63 isoform expression is linked with distinct clinical outcomes in cancer. EBioMedicine. 2020;51:102561.

    PubMed  PubMed Central  Google Scholar 

  114. Papadimitriou M-A, Avgeris M, Levis PK, Tokas T, Stravodimos K, Scorilas A. ΔNp63 transcript loss in bladder cancer constitutes an independent molecular predictor of TaT1 patients post-treatment relapse and progression. J Cancer Res Clin Oncol. 2019;145:3075–87.

    CAS  PubMed  Google Scholar 

  115. Guo CC, Majewski T, Zhang L, Yao H, Bondaruk J, Wang Y, et al. Dysregulation of EMT drives the progression to clinically aggressive sarcomatoid bladder cancer. Cell Rep. 2019;27:1781–.e4.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Eckert D, Buhl S, Weber S, Jäger R, Schorle H. The AP-2 family of transcription factors. Genome Biol. 2005;6:246.

    PubMed  PubMed Central  Google Scholar 

  117. Sinha S, Fuchs E. Identification and dissection of an enhancer controlling epithelial gene expression in skin. Proc Natl Acad Sci USA. 2001;98:2455–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Kaufman CK, Sinha S, Bolotin D, Fan J, Fuchs E. Dissection of a complex enhancer element: maintenance of keratinocyte specificity but loss of differentiation specificity. Mol Cell Biol. 2002;22:4293–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Leask A, Byrne C, Fuchs E. Transcription factor AP2 and its role in epidermal-specific gene expression. Proc Natl Acad Sci USA. 1991;88:7948–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. McDade SS, Henry AE, Pivato GP, Kozarewa I, Mitsopoulos C, Fenwick K, et al. Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation. Nucleic Acids Res. 2012;40:7190–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Yamashita H, Kawasawa YI, Shuman L, Zheng Z, Tran T, Walter V, et al. Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer. Oncogenesis. 2019;8:69.

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Davis AC, Wims M, Spotts GD, Hann SR, Bradley A. A null c-myc mutation causes lethality before 10.5 days of gestation in homozygotes and reduced fertility in heterozygous female mice. Genes Dev. 1993;7:671–82.

    CAS  PubMed  Google Scholar 

  123. Watters AD, Latif Z, Forsyth A, Dunn I, Underwood MA, Grigor KM, et al. Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer. Br J Cancer. 2002;87:654–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Li Y, Liu H, Lai C, Du X, Su Z, Gao S. The Lin28/let-7a/c-Myc pathway plays a role in non-muscle invasive bladder cancer. Cell Tissue Res. 2013;354:533–41.

    CAS  PubMed  Google Scholar 

  125. Mahe M, Dufour F, Neyret-Kahn H, Moreno-Vega A, Beraud C, Shi M, et al. An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers. EMBO Mol Med. 2018;10:e8163.

    PubMed  PubMed Central  Google Scholar 

  126. Zhuang C, Ma Q, Zhuang C, Ye J, Zhang F, Gui Y. LncRNA GClnc1 promotes proliferation and invasion of bladder cancer through activation of MYC. FASEB J. 2019;33:11045–59.

    CAS  PubMed  Google Scholar 

  127. Jiang G, Huang C, Liao X, Li J, Wu X-R, Zeng F, et al. The RING domain in the anti-apoptotic protein XIAP stabilizes c-Myc protein and preserves anchorage-independent growth of bladder cancer cells. J Biol Chem. 2019;294:5935–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Robertson AG, Groeneveld CS, Jordan B, Lin X, McLaughlin KA, Das A, et al. Identification of differential tumor subtypes of T1 bladder cancer. Eur Urol. 2020;78:533–7.

    CAS  PubMed  Google Scholar 

  129. Fontugne J, Wong J, Cabel L, Neyret-Kahn H, Karboul N, Maillé P, et al. Progression-associated molecular changes in basal/squamous and sarcomatoid bladder carcinogenesis. J Pathol. 2023;259:455–67.

    CAS  PubMed  Google Scholar 

  130. Marquis L, Tran M, Choi W, Lee I-L, Huszar D, Siefker-Radtke A, et al. p63 expression correlates with sensitivity to the Eg5 inhibitor ZD4877 in bladder cancer cells. Cancer Biol Ther. 2012;13:477–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Greife A, Jankowiak S, Steinbring J, Nikpour P, Niegisch G, Hoffmann MJ, et al. Canonical Notch signalling is inactive in urothelial carcinoma. BMC Cancer. 2014;14:628.

    PubMed  PubMed Central  Google Scholar 

  132. Paraskevopoulou V, Bonis V, Dionellis VS, Paschalidis N, Melissa P, Chavdoula E, et al. Notch controls urothelial integrity in the mouse bladder. JCI Insight. 2020;5:e133232.

    PubMed  PubMed Central  Google Scholar 

  133. Rampias T, Vgenopoulou P, Avgeris M, Polyzos A, Stravodimos K, Valavanis C, et al. A new tumor suppressor role for the Notch pathway in bladder cancer. Nat Med. 2014;20:1199–205.

    CAS  PubMed  Google Scholar 

  134. Maraver A, Fernandez-Marcos PJ, Cash TP, Mendez-Pertuz M, Dueñas M, Maietta P, et al. NOTCH pathway inactivation promotes bladder cancer progression. J Clin Investig. 2015;125:824–30.

    PubMed  PubMed Central  Google Scholar 

  135. Hayashi T, Gust KM, Wyatt AW, Goriki A, Jäger W, Awrey S, et al. Not all NOTCH is created equal: the oncogenic role of NOTCH2 in bladder cancer and its implications for targeted therapy. Clin Cancer Res. 2016;22:2981–92.

    CAS  PubMed  Google Scholar 

  136. Zhang L, Sha J, Yang G, Huang X, Bo J, Huang Y. Activation of Notch pathway is linked with epithelial-mesenchymal transition in prostate cancer cells. Cell Cycle. 2017;16:999–1007.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Watabe T, Yoshida K, Shindoh M, Kaya M, Fujikawa K, Sato H, et al. The Ets-1 and Ets-2 transcription factors activate the promoters for invasion-associated urokinase and collagenase genes in response to epidermal growth factor. Int J Cancer. 1998;77:128–37.

    CAS  PubMed  Google Scholar 

  138. Westermarck J, Seth A, Kähäri VM. Differential regulation of interstitial collagenase (MMP-1) gene expression by ETS transcription factors. Oncogene. 1997;14:2651–60.

    CAS  PubMed  Google Scholar 

  139. Hashiya N, Jo N, Aoki M, Matsumoto K, Nakamura T, Sato Y, et al. In vivo evidence of angiogenesis induced by transcription factor Ets-1: Ets-1 is located upstream of angiogenesis cascade. Circulation. 2004;109:3035–41.

    CAS  PubMed  Google Scholar 

  140. Sari A, Calli A, Gorgel SN, Altinboga AA, Kara C, Dincel C, et al. Immunohistochemical determination of ETS-1 oncoprotein expression in urothelial carcinomas of the urinary bladder. Appl Immunohistochem Mol Morphol. 2012;20:153–8.

    CAS  PubMed  Google Scholar 

  141. Liu L, Liu Y, Zhang X, Chen M, Wu H, Lin M, et al. Inhibiting cell migration and cell invasion by silencing the transcription factor ETS-1 in human bladder cancer. Oncotarget. 2016;7:25125–34.

    PubMed  PubMed Central  Google Scholar 

  142. Lin S-R, Yeh H-C, Wang W-J, Ke H-L, Lin H-H, Hsu W-C, et al. MiR-193b mediates CEBPD-induced cisplatin sensitization through targeting ETS1 and cyclin D1 in human urothelial carcinoma cells. J Cell Biochem. 2017;118:1563–73.

    CAS  PubMed  Google Scholar 

  143. Shin S-S, Park S-S, Hwang B, Kim WT, Choi YH, Kim W-J, et al. MicroRNA-106a suppresses proliferation, migration, and invasion of bladder cancer cells by modulating MAPK signaling, cell cycle regulators, and Ets-1-mediated MMP-2 expression. Oncol Rep. 2016;36:2421–9.

    CAS  PubMed  Google Scholar 

  144. Bell SM, Zhang L, Mendell A, Xu Y, Haitchi HM, Lessard JL, et al. Kruppel-like factor 5 is required for formation and differentiation of the bladder urothelium. Dev Biol. 2011;358:79–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Zhang B, Li Y, Wu Q, Xie L, Barwick B, Fu C, et al. Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer. Nat Commun. 2021;12:1714.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Du C, Gao Y, Xu S, Jia J, Huang Z, Fan J, et al. KLF5 promotes cell migration by up-regulating FYN in bladder cancer cells. FEBS Lett. 2016;590:408–18.

    CAS  PubMed  Google Scholar 

  147. Gao Y, Wu K, Chen Y, Zhou J, Du C, Shi Q, et al. Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription. Oncotarget. 2015;6:43791–805.

    PubMed  PubMed Central  Google Scholar 

  148. Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, et al. Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem Biophys Res Commun. 2003;308:251–6.

    CAS  PubMed  Google Scholar 

  149. Li H, Wang J, Xiao W, Xia D, Lang B, Wang T, et al. Epigenetic inactivation of KLF4 is associated with urothelial cancer progression and early recurrence. J Urol. 2014;191:493–501.

    CAS  PubMed  Google Scholar 

  150. Ai X, Jia Z, Liu S, Wang J, Zhang X. Notch-1 regulates proliferation and differentiation of human bladder cancer cell lines by inhibiting expression of Krüppel-like factor 4. Oncol Rep. 2014;32:1459–64.

    CAS  PubMed  Google Scholar 

  151. Xu X, Li J, Zhu Y, Xie B, Wang X, Wang S, et al. CRISPR-ON-Mediated KLF4 overexpression inhibits the proliferation, migration and invasion of urothelial bladder cancer in vitro and in vivo. Oncotarget. 2017;8:102078–87.

    PubMed  PubMed Central  Google Scholar 

  152. Suske G. The Sp-family of transcription factors. Gene. 1999;238:291–300.

    CAS  PubMed  Google Scholar 

  153. Hagen G, Müller S, Beato M, Suske G. Sp1-mediated transcriptional activation is repressed by Sp3. EMBO J. 1994;13:3843–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Xu J, Hua X, Yang R, Jin H, Li J, Zhu J, et al. XIAP Interaction with E2F1 and Sp1 via its BIR2 and BIR3 domains specific activated MMP2 to promote bladder cancer invasion. Oncogenesis. 2019;8:71.

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Huang H, Jin H, Zhao H, Wang J, Li X, Yan H, et al. RhoGDIβ promotes Sp1/MMP-2 expression and bladder cancer invasion through perturbing miR-200c-targeted JNK2 protein translation. Mol Oncol. 2017;11:1579–94.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Zhu J, Lu Z, Ke M, Cai X. Sp1 is overexpressed and associated with progression and poor prognosis in bladder urothelial carcinoma patients. Int Urol Nephrol. 2022;54:1505–12.

    CAS  PubMed  Google Scholar 

  157. Malats N, Real FX. Epidemiology of bladder cancer. Hematol. Oncol. Clin. North Am. 2015;29:177–89.

  158. Caliri AW, Tommasi S, Besaratinia A. Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer. Mutat Res Rev Mutat Res. 2021;787:108365.

    CAS  PubMed  Google Scholar 

  159. Denison MS, Nagy SR. Activation of the aryl hydrocarbon receptor by structurally diverse exogenous and endogenous chemicals. Annu Rev Pharm Toxicol. 2003;43:309–34.

    CAS  Google Scholar 

  160. Pollenz RS, Sattler CA, Poland A. The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. Mol Pharm. 1994;45:428–38.

    CAS  Google Scholar 

  161. Hord NG, Perdew GH. Physicochemical and immunocytochemical analysis of the aryl hydrocarbon receptor nuclear translocator: characterization of two monoclonal antibodies to the aryl hydrocarbon receptor nuclear translocator. Mol Pharm. 1994;46:618–26.

    CAS  Google Scholar 

  162. Soshilov AA, Motta S, Bonati L, Denison MS. Transitional states in ligand-dependent transformation of the aryl hydrocarbon receptor into its DNA-binding form. Int J Mol Sci. 2020;21:2474.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Yu J, Lu Y, Muto S, Ide H, Horie S. The dual function of aryl hydrocarbon receptor in bladder carcinogenesis. Anticancer Res. 2020;40:1345–57.

    CAS  PubMed  Google Scholar 

  164. Baker SC, Arlt VM, Indra R, Joel M, Stiborová M, Eardley I, et al. Differentiation-associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic-metabolizing activity of “luminal” muscle-invasive bladder cancers. Mol Carcinog. 2018;57:606–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Vlaar JM, Borgman A, Kalkhoven E, Westland D, Besselink N, Shale C, et al. Recurrent exon-deleting activating mutations in AHR act as drivers of urinary tract cancer. Sci Rep. 2022;12:10081.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Huang HC, Nguyen T, Pickett CB. Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA. 2000;97:12475–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Hayashi M, Guida E, Inokawa Y, Goldberg R, Reis LO, Ooki A, et al. GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma. Sci Signal. 2020;13:eaba0443.

    CAS  PubMed  Google Scholar 

  168. Ihara T, Mitsui T, Nakamura Y, Kanda M, Tsuchiya S, Kira S, et al. The oscillation of intracellular Ca2+ influx associated with the circadian expression of Piezo1 and TRPV4 in the bladder urothelium. Sci Rep. 2018;8:5699.

    PubMed  PubMed Central  Google Scholar 

  169. Litlekalsoy J, Rostad K, Kalland K-H, Hostmark JG, Laerum OD. Expression of circadian clock genes and proteins in urothelial cancer is related to cancer-associated genes. BMC Cancer. 2016;16:549.

    PubMed  PubMed Central  Google Scholar 

  170. Honma S, Kawamoto T, Takagi Y, Fujimoto K, Sato F, Noshiro M, et al. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature. 2002;419:841–4.

    CAS  PubMed  Google Scholar 

  171. Cobo I, Martinelli P, Flández M, Bakiri L, Zhang M, Carrillo-de-Santa-Pau E, et al. Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature. 2018;554:533–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Bejjani F, Evanno E, Zibara K, Piechaczyk M, Jariel-Encontre I. The AP-1 transcriptional complex: Local switch or remote command? Biochim Biophys Acta Rev Cancer. 2019;1872:11–23.

    CAS  PubMed  Google Scholar 

  173. Wang Y, Geng H, Zhao L, Zhang Z, Xie D, Zhang T, et al. Role of AP-1 in the tobacco smoke-induced urocystic abnormal cell differentiation and epithelial-mesenchymal transition in vivo. Int J Clin Exp Pathol. 2017;10:8243–52.

    PubMed  PubMed Central  Google Scholar 

  174. Barrows D, Feng L, Carroll TS, Allis CD. Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer. Proc Natl Acad Sci USA. 2020;117:25732–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Qiu H, Makarov V, Bolzenius JK, Halstead A, Parker Y, Wang A, et al. KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer. Cancer Res. 2023;83:814–29.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Neyret-Kahn H, Fontugne J, Meng XY, Groeneveld CS, Cabel L, Ye T, et al. Epigenomic mapping identifies an enhancer repertoire that regulates cell identity in bladder cancer through distinct transcription factor networks. Oncogene. 2023;42:1524–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Cai Z, Chen H, Bai J, Zheng Y, Ma J, Cai X, et al. Copy number variations of CEP63, FOSL2 and PAQR6 serve as novel signatures for the prognosis of bladder cancer. Front Oncol. 2021;11:674933.

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Iwata J, Suzuki A, Pelikan RC, Ho T-V, Sanchez-Lara PA, Urata M, et al. Smad4-Irf6 genetic interaction and TGFβ-mediated IRF6 signaling cascade are crucial for palatal fusion in mice. Development. 2013;140:1220–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Richardson RJ, Dixon J, Malhotra S, Hardman MJ, Knowles L, Boot-Handford RP, et al. Irf6 is a key determinant of the keratinocyte proliferation-differentiation switch. Nat Genet. 2006;38:1329–34.

    CAS  PubMed  Google Scholar 

  180. Restivo G, Nguyen B-C, Dziunycz P, Ristorcelli E, Ryan RJH, Özuysal ÖY, et al. IRF6 is a mediator of Notch pro-differentiation and tumour suppressive function in keratinocytes. EMBO J. 2011;30:4571–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Weng H, Yuan S, Huang Q, Zeng X-T, Wang X-H. STAT1 is a key gene in a gene regulatory network related to immune phenotypes in bladder cancer: An integrative analysis of multi-omics data. J Cell Mol Med. 2021;25:3258–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Su Q, Sun Y, Zhang Z, Yang Z, Qiu Y, Li X, et al. Identification of prognostic immune genes in bladder urothelial carcinoma. Biomed Res Int. 2020;2020:7510120.

    PubMed  PubMed Central  Google Scholar 

  183. Kawahara T, Ishiguro Y, Ohtake S, Kato I, Ito Y, Ito H, et al. PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer. BMC Urol. 2018;18:97.

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Huang W-T, Yang S-F, Wu C-C, Chen W-T, Huang Y-C, Su Y-C, et al. Expression of signal transducer and activator of transcription 3 and suppressor of cytokine signaling 3 in urothelial carcinoma. Kaohsiung J Med Sci. 2009;25:640–6.

    CAS  PubMed  Google Scholar 

  185. Hindupur SV, Schmid SC, Koch JA, Youssef A, Baur E-M, Wang D, et al. STAT3/5 inhibitors suppress proliferation in bladder cancer and enhance oncolytic adenovirus therapy. Int J Mol Sci. 2020;21:1106.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Gatta LB, Melocchi L, Bugatti M, Missale F, Lonardi S, Zanetti B, et al. Hyper-activation of STAT3 sustains progression of non-papillary basal-type bladder cancer via FOSL1 regulome. Cancers. 2019;11:1219.

    CAS  PubMed  Google Scholar 

  187. Ching CB, Gupta S, Li B, Cortado H, Mayne N, Jackson AR, et al. Interleukin-6/Stat3 signaling has an essential role in the host antimicrobial response to urinary tract infection. Kidney Int. 2018;93:1320–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Schneidewind L, Neumann T, Plis A, Brückmann S, Keiser M, Krüger W, et al. Novel 3D organotypic urothelial cell culture model for identification of new therapeutic approaches in urological infections. J Clin Virol. 2020;124:104283.

    CAS  PubMed  Google Scholar 

  189. Boorjian S, Ugras S, Mongan NP, Gudas LJ, You X, Tickoo SK, et al. Androgen receptor expression is inversely correlated with pathologic tumor stage in bladder cancer. Urology. 2004;64:383–8.

    PubMed  Google Scholar 

  190. Tuygun C, Kankaya D, Imamoglu A, Sertcelik A, Zengin K, Oktay M, et al. Sex-specific hormone receptors in urothelial carcinomas of the human urinary bladder: a comparative analysis of clinicopathological features and survival outcomes according to receptor expression. Urol Oncol. 2011;29:43–51.

    CAS  PubMed  Google Scholar 

  191. Miyamoto H, Yao JL, Chaux A, Zheng Y, Hsu I, Izumi K, et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 2012;109:1716–26.

    CAS  PubMed  Google Scholar 

  192. Miyamoto H, Yang Z, Chen Y-T, Ishiguro H, Uemura H, Kubota Y, et al. Promotion of bladder cancer development and progression by androgen receptor signals. J Natl Cancer Inst. 2007;99:558–68.

    CAS  PubMed  Google Scholar 

  193. Johnson AM, O’Connell MJ, Messing EM, Reeder JE. Decreased bladder cancer growth in parous mice. Urology. 2008;72:470–3.

    PubMed  Google Scholar 

  194. Shen SS, Smith CL, Hsieh J-T, Yu J, Kim IY, Jian W, et al. Expression of estrogen receptors-alpha and -beta in bladder cancer cell lines and human bladder tumor tissue. Cancer. 2006;106:2610–6.

    CAS  PubMed  Google Scholar 

  195. Hsu L-H, Liu K-J, Tsai M-F, Wu C-R, Feng A-C, Chu N-M, et al. Estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Cancer Sci. 2015;106:51–9.

    CAS  PubMed  Google Scholar 

  196. Ide H, Inoue S, Miyamoto H. Histopathological and prognostic significance of the expression of sex hormone receptors in bladder cancer: a meta-analysis of immunohistochemical studies. PLoS One. 2017;12:e0174746.

    PubMed  PubMed Central  Google Scholar 

  197. Warot X, Fromental-Ramain C, Fraulob V, Chambon P, Dollé P. Gene dosage-dependent effects of the Hoxa-13 and Hoxd-13 mutations on morphogenesis of the terminal parts of the digestive and urogenital tracts. Development. 1997;124:4781–91.

    CAS  PubMed  Google Scholar 

  198. Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997;15:179–80.

    CAS  PubMed  Google Scholar 

  199. Warrick JI, Knowles MA, Hurst CD, Shuman L, Raman JD, Walter V, et al. A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma. Sci Rep. 2022;12:16538.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Marzouka N-A-D, Eriksson P, Bernardo C, Hurst CD, Knowles MA, Sjödahl G, et al. The lund molecular taxonomy applied to non-muscle-invasive urothelial carcinoma. J Mol Diagn. 2022;24:992–1008.

    CAS  PubMed  Google Scholar 

  201. Lauss M, Aine M, Sjödahl G, Veerla S, Patschan O, Gudjonsson S, et al. DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status. Epigenetics. 2012;7:858–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Aine M, Sjödahl G, Eriksson P, Veerla S, Lindgren D, Ringnér M, et al. Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma. Genome Med. 2015;7:23.

    PubMed  PubMed Central  Google Scholar 

  203. Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006;20:1123–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Picchetti T, Chiquet J, Elati M, Neuvial P, Nicolle R, Birmelé E. A model for gene deregulation detection using expression data. BMC Syst Biol. 2015;9:S6.

    PubMed  PubMed Central  Google Scholar 

  205. Nicolle R, Radvanyi F, Elati M. CoRegNet: reconstruction and integrated analysis of co-regulatory networks. Bioinformatics. 2015;31:3066–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Champion M, Chiquet J, Neuvial P, Elati M, Radvanyi F, Birmelé E. Identification of deregulation mechanisms specific to cancer subtypes. J Bioinf Comput Biol. 2021;19:2140003.

    CAS  Google Scholar 

  207. Liang Y, Li L, Xin T, Li B, Zhang D. Superenhancer-transcription factor regulatory network in malignant tumors. Open Med (Wars). 2021;16:1564–82.

    CAS  PubMed  Google Scholar 

  208. Sfakianos JP, Daza J, Hu Y, Anastos H, Bryant G, Bareja R, et al. Epithelial plasticity can generate multi-lineage phenotypes in human and murine bladder cancers. Nat Commun. 2020;11:2540.

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Wang H, Mei Y, Luo C, Huang Q, Wang Z, Lu G-M, et al. Single-cell analyses reveal mechanisms of cancer stem cell maintenance and epithelial-mesenchymal transition in recurrent bladder cancer. Clin Cancer Res. 2021;27:6265–78.

    CAS  PubMed  Google Scholar 

  210. Wang K-J, Wang C, Dai L-H, Yang J, Huang H, Ma X-J, et al. Targeting an autocrine regulatory loop in cancer stem-like cells impairs the progression and chemotherapy resistance of bladder cancer. Clin Cancer Res. 2019;25:1070–86.

    CAS  PubMed  Google Scholar 

  211. Whitfield JR, Beaulieu M-E, Soucek L. Strategies to inhibit myc and their clinical applicability. Front Cell Dev Biol. 2017;5:10.

    PubMed  PubMed Central  Google Scholar 

  212. Beaulieu M-E, Jauset T, Massó-Vallés D, Martínez-Martín S, Rahl P, Maltais L, et al. Intrinsic cell-penetrating activity propels Omomyc from proof of concept to viable anti-MYC therapy. Sci Transl Med. 2019;11:eaar5012.

    PubMed  PubMed Central  Google Scholar 

  213. Lindskrog SV, Prip F, Lamy P, Taber A, Groeneveld CS, Birkenkamp-Demtröder K, et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat Commun. 2021;12:2301.

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics. Nat Chem Biol. 2019;15:937–44.

    CAS  PubMed  Google Scholar 

  215. Qi S-M, Dong J, Xu Z-Y, Cheng X-D, Zhang W-D, Qin J-J. PROTAC: an effective targeted protein degradation strategy for cancer therapy. Front Pharm. 2021;12:692574.

    CAS  Google Scholar 

  216. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    PubMed  PubMed Central  Google Scholar 

  217. Heinz S, Benner C, Spann N, Bertolino E, Lin YC, Laslo P, et al. Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell. 2010;38:576–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Brooks DJ, Woodward S, Thompson FH, Dos Santos B, Russell M, Yang JM, et al. Expression of the zinc finger gene EVI-1 in ovarian and other cancers. Br J Cancer. 1996;74:1518–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Inoue Y, Kishida T, Kotani S-I, Akiyoshi M, Taga H, Seki M, et al. Direct conversion of fibroblasts into urothelial cells that may be recruited to regenerating mucosa of injured urinary bladder. Sci Rep. 2019;9:13850.

    PubMed  PubMed Central  Google Scholar 

  220. Primdahl H, von der Maase H, Christensen M, Wolf H, Orntoft TF. Allelic deletions of cell growth regulators during progression of bladder cancer. Cancer Res. 2000;60:6623–9.

    CAS  PubMed  Google Scholar 

  221. Boorjian SA, Heemers HV, Frank I, Farmer SA, Schmidt LJ, Sebo TJ, et al. Expression and significance of androgen receptor coactivators in urothelial carcinoma of the bladder. Endocr Relat Cancer. 2009;16:123–37.

    CAS  PubMed  Google Scholar 

  222. Dozmorov M, Stone R, Clifford JL, Sabichi AL, Engles CD, Hauser PJ, et al. System level changes in gene expression in maturing bladder mucosa. J Urol. 2011;185:1952–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Zhang Y, Dufau ML. Nuclear orphan receptors regulate transcription of the gene for the human luteinizing hormone receptor. J Biol Chem. 2000;275:2763–70.

    CAS  PubMed  Google Scholar 

  224. Hermann-Kleiter N, Gruber T, Lutz-Nicoladoni C, Thuille N, Fresser F, Labi V, et al. The nuclear orphan receptor NR2F6 suppresses lymphocyte activation and T helper 17-dependent autoimmunity. Immunity. 2008;29:205–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Du X, Wang Q-R, Chan E, Merchant M, Liu J, French D, et al. FGFR3 stimulates stearoyl CoA desaturase 1 activity to promote bladder tumor growth. Cancer Res. 2012;72:5843–55.

    CAS  PubMed  Google Scholar 

  226. Fu Y, Sun S, Bi J, Kong C, Yin L. Construction and analysis of a ceRNA network and patterns of immune infiltration in bladder cancer. Transl Androl Urol. 2021;10:1939–55.

    PubMed  PubMed Central  Google Scholar 

  227. Jiang A, Liu N, Bai S, Wang J, Gao H, Zheng X, et al. The construction and analysis of tumor-infiltrating immune cells and ceRNA networks in bladder cancer. Front Genet. 2020;11:605767.

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Papaioannou VE. The T-box gene family: emerging roles in development, stem cells and cancer. Development. 2014;141:3819–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Lingbeek ME, Jacobs JJL, van Lohuizen M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem. 2002;277:26120–7.

    CAS  PubMed  Google Scholar 

  230. Peres J, Davis E, Mowla S, Bennett DC, Li JA, Wansleben S, et al. The highly homologous T-box transcription Factors, TBX2 and TBX3, have distinct roles in the oncogenic process. Genes Cancer. 2010;1:272–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Ichijo R, Kobayashi H, Yoneda S, Iizuka Y, Kubo H, Matsumura S, et al. Tbx3-dependent amplifying stem cell progeny drives interfollicular epidermal expansion during pregnancy and regeneration. Nat Commun. 2017;8:508.

    PubMed  PubMed Central  Google Scholar 

  232. Ito A, Asamoto M, Hokaiwado N, Takahashi S, Shirai T. Tbx3 expression is related to apoptosis and cell proliferation in rat bladder both hyperplastic epithelial cells and carcinoma cells. Cancer Lett. 2005;219:105–12.

    CAS  PubMed  Google Scholar 

  233. Aydogdu N, Rudat C, Trowe M-O, Kaiser M, Lüdtke TH, Taketo MM, et al. TBX2 and TBX3 act downstream of canonical WNT signaling in patterning and differentiation of the mouse ureteric mesenchyme. Development. 2018;145:dev171827.

    PubMed  Google Scholar 

  234. Shi Z, Li X, Wu D, Tang R, Chen R, Xue S, et al. Silencing of HMGA2 suppresses cellular proliferation, migration, invasion, and epithelial-mesenchymal transition in bladder cancer. Tumour Biol. 2016;37:7515–23.

    CAS  PubMed  Google Scholar 

  235. Chen Z, Li Q, Wang S, Zhang J. miR-485-5p inhibits bladder cancer metastasis by targeting HMGA2. Int J Mol Med. 2015;36:1136–42.

    CAS  PubMed  Google Scholar 

  236. Ding X, Wang Y, Ma X, Guo H, Yan X, Chi Q, et al. Expression of HMGA2 in bladder cancer and its association with epithelial-to-mesenchymal transition. Cell Prolif. 2014;47:146–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Zhang Y, Luo G, You S, Zhang L, Liang C, Chen X. Exosomal LINC00355 derived from cancer-associated fibroblasts promotes bladder cancer cell proliferation and invasion by regulating miR-15a-5p/HMGA2 axis. Acta Biochim Biophys Sin. 2021;53:673–82.

    CAS  PubMed  Google Scholar 

  238. Zhuang J, Shen L, Yang L, Huang X, Lu Q, Cui Y, et al. TGFβ1 promotes gemcitabine resistance through regulating the LncRNA-LET/NF90/miR-145 signaling axis in bladder cancer. Theranostics. 2017;7:3053–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Zheng Y, Izumi K, Yao JL, Miyamoto H. Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells. Endocr Relat Cancer. 2011;18:451–64.

    CAS  PubMed  Google Scholar 

  240. Xu C, Sun M, Zhang X, Xu Z, Miyamoto H, Zheng Y. Activation of glucocorticoid receptor inhibits the stem-like properties of bladder cancer via inactivating the β-catenin pathway. Front Oncol. 2020;10:1332.

    PubMed  PubMed Central  Google Scholar 

  241. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 2002;21:5216–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Kanno H, Ozawa H, Dohi Y, Sekiguchi A, Igarashi K, Itoi E. Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice. J Neurotrauma. 2009;26:31–9.

    PubMed  Google Scholar 

  243. Somerville TDD, Xu Y, Wu XS, Maia-Silva D, Hur SK, de Almeida LMN, et al. ZBED2 is an antagonist of interferon regulatory factor 1 and modifies cell identity in pancreatic cancer. Proc Natl Acad Sci USA. 2020;117:11471–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Finnegan A, Cho RJ, Luu A, Harirchian P, Lee J, Cheng JB, et al. Single-cell transcriptomics reveals spatial and temporal turnover of keratinocyte differentiation regulators. Front Genet. 2019;10:775.

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Fossum SL, Mutolo MJ, Tugores A, Ghosh S, Randell SH, Jones LC, et al. Ets homologous factor (EHF) has critical roles in epithelial dysfunction in airway disease. J Biol Chem. 2017;292:10938–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Asai T, Morrison SL. The SRC family tyrosine kinase HCK and the ETS family transcription factors SPIB and EHF regulate transcytosis across a human follicle-associated epithelium model. J Biol Chem. 2013;288:10395–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Rubin AJ, Barajas BC, Furlan-Magaril M, Lopez-Pajares V, Mumbach MR, Howard I, et al. Lineage-specific dynamic and pre-established enhancer-promoter contacts cooperate in terminal differentiation. Nat Genet. 2017;49:1522–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Shi J, Qu Y, Li X, Sui F, Yao D, Yang Q, et al. Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer. Cell Death Dis. 2016;7:e2442.

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Taniue K, Oda T, Hayashi T, Okuno M, Akiyama T. A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis. EMBO Rep. 2011;12:682–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Lv Y, Sui F, Ma J, Ren X, Yang Q, Zhang Y, et al. Increased expression of EHF contributes to thyroid tumorigenesis through transcriptionally regulating HER2 and HER3. Oncotarget. 2016;7:57978–90.

    PubMed  PubMed Central  Google Scholar 

  251. Cheng Z, Guo J, Chen L, Luo N, Yang W, Qu X. Knockdown of EHF inhibited the proliferation, invasion and tumorigenesis of ovarian cancer cells. Mol Carcinog. 2016;55:1048–59.

    CAS  PubMed  Google Scholar 

  252. Cangemi R, Mensah A, Albertini V, Jain A, Mello-Grand M, Chiorino G, et al. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene. 2008;27:2877–85.

    CAS  PubMed  Google Scholar 

  253. Zhao T, Jiang W, Wang X, Wang H, Zheng C, Li Y, et al. ESE3 inhibits pancreatic cancer metastasis by upregulating E-cadherin. Cancer Res. 2017;77:874–85.

    CAS  PubMed  Google Scholar 

  254. Wang L, Xing J, Cheng R, Shao Y, Li P, Zhu S, et al. Abnormal localization and tumor suppressor function of epithelial tissue-specific transcription factor ESE3 in esophageal squamous cell carcinoma. PLoS One. 2015;10:e0126319.

    PubMed  PubMed Central  Google Scholar 

  255. Fisher WG, Yang P-C, Medikonduri RK, Jafri MS. NFAT and NFkappaB activation in T lymphocytes: a model of differential activation of gene expression. Ann Biomed Eng. 2006;34:1712–28.

    PubMed  PubMed Central  Google Scholar 

  256. Lee JH, Kim M, Im YS, Choi W, Byeon SH, Lee HK. NFAT5 induction and its role in hyperosmolar stressed human limbal epithelial cells. Investig Ophthalmol Vis Sci. 2008;49:1827–35.

    Google Scholar 

  257. Johnsen O, Skammelsrud N, Luna L, Nishizawa M, Prydz H, Kolstø AB. Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1. Nucleic Acids Res. 1996;24:4289–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Johnsen O, Murphy P, Prydz H, Kolsto AB. Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription. Nucleic Acids Res. 1998;26:512–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Steffen J, Seeger M, Koch A, Krüger E. Proteasomal degradation is transcriptionally controlled by TCF11 via an ERAD-dependent feedback loop. Mol Cell. 2010;40:147–58.

    CAS  PubMed  Google Scholar 

  260. Cui M, Atmanli A, Morales MG, Tan W, Chen K, Xiao X, et al. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance. Nat Commun. 2021;12:5270.

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Xu Z, Chen L, Leung L, Yen TSB, Lee C, Chan JY. Liver-specific inactivation of the Nrf1 gene in adult mouse leads to nonalcoholic steatohepatitis and hepatic neoplasia. Proc Natl Acad Sci USA. 2005;102:4120–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Lu Q, Qiufang Y, Peng L, Xiaowen Z, Yonghui Y.Xiuman Z,et al. Function expansion of antitumor transcriptional activator NFE2L1 by the original discovery of its non-transcription factor activity. BioRxiv. 2020; https://doi.org/10.1101/2020.10.08.330597.

  263. Xia W, Li Y, Wu Z, Wang Y, Xing N, Yang W, et al. Transcription factor YY1 mediates epithelial-mesenchymal transition through the TGFβ signaling pathway in bladder cancer. Med Oncol. 2020;37:93.

    CAS  PubMed  Google Scholar 

  264. Chen W, Jiang T, Mao H, Gao R, Gao X, He Y, et al. Nodal promotes the migration and invasion of bladder cancer cells via regulation of snail. J Cancer. 2019;10:1511–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Li J, Xu X, Meng S, Liang Z, Wang X, Xu M, et al. MET/SMAD3/SNAIL circuit mediated by miR-323a-3p is involved in regulating epithelial-mesenchymal transition progression in bladder cancer. Cell Death Dis. 2017;8:e3010.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank David McConkey and Andrew Mason for critical review of a previous version of the manuscript, Jaime Martínez de Villarreal and other members of the Epithelial Carcinogenesis Group for valuable contributions.

Funding

This work was supported, in part, by a grant from Fundación Científica de la Asociación Española Contra el Cáncer to FXR and EL (PRYGN223005REAL). The project that gave rise to these results received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is LCF/BQ/DR20/11790014. SC was supported by Fellowship PRE2018-085808 from Agencia Estatal de Investigación, co-financed by Fondo Social Europeo. CNIO is supported by Ministerio de Ciencia, Innovación y Universidades as a Centro de Excelencia Severo Ochoa SEV-2015-0510.

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Authors and Affiliations

  1. Epithelial Carcinogenesis Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain

    Maria Ramal, Sonia Corral, Mark Kalisz, Eleonora Lapi & Francisco X. Real

  2. CIBERONC, Madrid, Spain

    Mark Kalisz, Eleonora Lapi & Francisco X. Real

  3. Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain

    Francisco X. Real

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  1. Maria Ramal
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  2. Sonia Corral
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All authors reviewed and summarized literature on the topic. MR also performed new bioinformatics analyses included in the manuscript. SC took the main responsibility for the illustrations.

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Correspondence to Francisco X. Real.

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Ramal, M., Corral, S., Kalisz, M. et al. The urothelial gene regulatory network: understanding biology to improve bladder cancer management. Oncogene 43, 1–21 (2024). https://doi.org/10.1038/s41388-023-02876-3

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