Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer

Nature Reviews Urology volume 14, pages 98–106 (2017)Cite this article

Subjects

Key Points

  • Several molecular characterization studies have identified members of the forkhead box (FOX) superfamily of transcription factors as being differentially expressed in molecular subtypes of bladder cancer

  • As several of these FOX proteins are also involved in urothelial development and/or differentiation, these findings suggest that they might have a potential direct function in bladder cancer pathophysiology

  • Differential expression of several FOX family members, including FOXA1, is associated with clinical outcomes in patients with bladder cancer

  • Basic science studies have confirmed roles for some specific FOX proteins in bladder cancer

  • Further investigation is required to determine the extent and mechanism by which these transcription factors might directly contribute to tumour initiation, progression and responses to standard and emerging therapies

Abstract

Genomic and transcriptional studies have identified discrete molecular subtypes of bladder cancer. These observations could be the starting point to identify new treatments. Several members of the forkhead box (FOX) superfamily of transcription factors have been found to be differentially expressed in the different bladder cancer subtypes. In addition, the FOXA protein family are key regulators of embryonic bladder development and patterning. Both experimental and clinical data support a role for FOXA1 and FOXA2 in urothelial carcinoma. FOXA1 is expressed in embryonic and adult urothelium and its expression is altered in urothelial carcinomas and across disparate molecular bladder cancer subtypes. FOXA2 is normally absent from the adult urothelium, but developmental studies identified FOXA2 as a marker of a transient urothelial progenitor cell population during bladder development. Studies also implicate FOXA2 in bladder cancer and several other FOX proteins might be involved in development and/or progression of this disease; for example, FOXA1 and FOXO3A have been associated with clinical patient outcomes. Future studies should investigate to what extent and by which mechanisms FOX proteins might be directly involved in bladder cancer pathogenesis and treatment responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Heat map of FOX gene expression in bladder cancer molecular subtypes according to TCGA data.
Figure 2: Potential roles of FOX family members in bladder cancer pathogenesis.

Similar content being viewed by others

References

  1. Jürgens, G. & Weigel, D. Terminal versus segmental development in the Drosophila embryo — the role of the homeotic gene fork head. Rouxs Arch. Dev. Biol. 197, 345–354 (1988).

    Article  PubMed  Google Scholar 

  2. Weigel, D., Jurgens, G., Kuttner, F., Seifert, E. & Jackle, H. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell 57, 645–658 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Weigel, D. & Jackle, H. The fork head domain: a novel DNA binding motif of eukaryotic transcription factors? Cell 63, 455–456 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Lai, E. et al. HNF-3A, a hepatocyte-enriched transcription factor of novel structure is regulated transcriptionally. Genes Dev. 4, 1427–1436 (1990).

    Article  CAS  PubMed  Google Scholar 

  5. Jackson, B. C., Carpenter, C., Nebert, D. W. & Vasiliou, V. Update of human and mouse forkhead box (FOX) gene families. Hum. Genomics 4, 345–352 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hannenhalli, S. & Kaestner, K. H. The evolution of Fox genes and their role in development and disease. Nat. Rev. Genet. 10, 233–240 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Katoh, M., Igarashi, M., Fukuda, H., Nakagama, H. & Katoh, M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 328, 198–206 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Lam, E. W., Brosens, J. J., Gomes, A. R. & Koo, C. Y. Forkhead box proteins: tuning forks for transcriptional harmony. Nat. Rev. Cancer 13, 482–495 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Le Lay, J. & Kaestner, K. H. The Fox genes in the liver: from organogenesis to functional integration. Physiol. Rev. 90, 1–22 (2010).

    Article  CAS  PubMed  Google Scholar 

  10. Myatt, S. S. & Lam, E. W. The emerging roles of forkhead box (Fox) proteins in cancer. Nat. Rev. Cancer 7, 847–859 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Georgas, K. M. et al. An illustrated anatomical ontology of the developing mouse lower urogenital tract. Development 142, 1893–1908 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gandhi, D. et al. Retinoid signaling in progenitors controls specification and regeneration of the urothelium. Dev. Cell 26, 469–482 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baskin, L. S. et al. Cellular signaling in the bladder. Front. Biosci. 2, d592–d595 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Cunha, G. R. & Lung, B. The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J. Exp. Zool. 205, 181–193 (1978).

    Article  CAS  PubMed  Google Scholar 

  16. Master, V. A., Wei, G., Liu, W. & Baskin, L. S. Urothlelium facilitates the recruitment and trans-differentiation of fibroblasts into smooth muscle in acellular matrix. J. Urol. 170, 1628–1632 (2003).

    Article  PubMed  Google Scholar 

  17. Thomas, J. C. et al. Temporal–spatial protein expression in bladder tissue derived from embryonic stem cells. J. Urol. 180, 1784–1789 (2008).

    Article  PubMed  Google Scholar 

  18. Oottamasathien, S. et al. Directed differentiation of embryonic stem cells into bladder tissue. Dev. Biol. 304, 556–566 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cheng, W. et al. Sonic Hedgehog mediator Gli2 regulates bladder mesenchymal patterning. J. Urol. 180, 1543–1550 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Haraguchi, R. et al. Molecular analysis of coordinated bladder and urogenital organ formation by Hedgehog signaling. Development 134, 525–533 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Shiroyanagi, Y. et al. Urothelial sonic hedgehog signaling plays an important role in bladder smooth muscle formation. Differentiation 75, 968–977 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. DeGraff, D. J. et al. Loss of the urothelial differentiation marker FOXA1 is associated with high grade, late stage bladder cancer and increased tumor proliferation. PLoS ONE 7, e36669 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kopachik, W., Hayward, S. W. & Cunha, G. R. Expression of hepatocyte nuclear factor-3α in rat prostate, seminal vesicle, and bladder. Dev. Dyn. 211, 131–140 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Varley, C. L., Bacon, E. J., Holder, J. C. & Southgate, J. FOXA1 and IRF-1 intermediary transcriptional regulators of PPARγ-induced urothelial cytodifferentiation. Cell Death Differ. 16, 103–114 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. DeGraff, D. J. et al. When urothelial differentiation pathways go wrong: implications for bladder cancer development and progression. Urol. Oncol. 31, 802–811 (2013).

    Article  CAS  PubMed  Google Scholar 

  26. Huang, H. Y. et al. Persistent uroplakin expression in advanced urothelial carcinomas: implications in urothelial tumor progression and clinical outcome. Hum. Pathol. 38, 1703–1713 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lobban, E. D. et al. Uroplakin gene expression by normal and neoplastic human urothelium. Am. J. Pathol. 153, 1957–1967 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Olsburgh, J. et al. Uroplakin gene expression in normal human tissues and locally advanced bladder cancer. J. Pathol. 199, 41–49 (2003).

    Article  PubMed  CAS  Google Scholar 

  29. Wu, R. L. et al. Uroplakin II gene is expressed in transitional cell carcinoma but not in bilharzial bladder squamous cell carcinoma: alternative pathways of bladder epithelial differentiation and tumor formation. Cancer Res. 58, 1291–1297 (1998).

    CAS  PubMed  Google Scholar 

  30. Liang, F. X. et al. Cellular basis of urothelial squamous metaplasia: roles of lineage heterogeneity and cell replacement. J. Cell Biol. 171, 835–844 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Reddy, O. L. 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. 185, 1385–1395 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Raman, J. D. et al. Altered expression of the transcription factor forkhead box A1 (FOXA1) is associated with poor prognosis in urothelial carcinoma of the upper urinary tract. Urology 94, 314.e1–314.e7 (2016).

    Article  Google Scholar 

  33. Harnden, P. & Southgate, J. Cytokeratin 14 as a marker of squamous differentiation in transitional cell carcinomas. J. Clin. Pathol. 50, 1032–1033 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Strand, D. W. et al. Deficiency in metabolic regulators PPARγ and PTEN cooperates to drive keratinizing squamous metaplasia in novel models of human tissue regeneration. Am. J. Pathol. 182, 449–459 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Sjodahl, G. et al. A molecular taxonomy for urothelial carcinoma. Clin. Cancer Res. 18, 3377–3386 (2012).

    Article  CAS  PubMed  Google Scholar 

  36. Choi, W. et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell 25, 152–165 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

  38. Damrauer, J. S. et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc. Natl Acad. Sci. USA 111, 3110–3115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Varley, C. L., Stahlschmidt, J., Smith, B., Stower, M. & Southgate, J. Activation of peroxisome proliferator-activated receptor-γ reverses squamous metaplasia and induces transitional differentiation in normal human urothelial cells. Am. J. Pathol. 164, 1789–1798 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Rebouissou, S. et al. EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype. Sci. Transl Med. 6, 244ra91 (2014).

    Article  PubMed  CAS  Google Scholar 

  41. Wang, I. C. et al. Forkhead box M1 regulates the transcriptional network of genes essential for mitotic progression and genes encoding the SCF (Skp2-Cks1) ubiquitin ligase. Mol. Cell. Biol. 25, 10875–10894 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang, X., Kiyokawa, H., Dennewitz, M. B. & Costa, R. H. The forkhead box m1b transcription factor is essential for hepatocyte DNA replication and mitosis during mouse liver regeneration. Proc. Natl Acad. Sci. USA 99, 16881–16886 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wang, X. et al. Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc. Natl Acad. Sci. USA 98, 11468–11473 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu, D., Zhang, Z. & Kong, C. Z. High FOXM1 expression was associated with bladder carcinogenesis. Tumour Biol. 34, 1131–1138 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Kim, S. K. et al. Expression signature defined by FOXM1–CCNB1 activation predicts disease recurrence in non-muscle-invasive bladder cancer. Clin. Cancer Res. 20, 3233–3243 (2014).

    Article  CAS  PubMed  Google Scholar 

  46. Eriksson, P. et al. Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems. BMC Med. Genomics 8, 25 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Pignot, G. et al. Hedgehog pathway activation in human transitional cell carcinoma of the bladder. Br. J. Cancer 106, 1177–1186 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Shin, K. et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell 26, 521–533 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Van Batavia, J. et al. Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 16, 982–991 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Zhang, J., Yuan, C., Wu, J., Elsayed, Z. & Fu, Z. Polo-like kinase 1-mediated phosphorylation of forkhead box protein M1b antagonizes its SUMOylation and facilitates its mitotic function. J. Biol. Chem. 290, 3708–3719 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Brassesco, M. S. et al. In vitro targeting of polo-like kinase 1 in bladder carcinoma: comparative effects of four potent inhibitors. Cancer Biol. Ther. 14, 648–657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zhang, X. et al. A novel FOXM1 isoform, FOXM1D, promotes epithelial–mesenchymal transition and metastasis through ROCKs activation in colorectal cancer. Oncogene http://dx.doi.org/10.1038/onc.2016.249 (2016).

  53. Lin, S. C. et al. Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat. Commun. 7, 11418 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Meng, F. D. et al. FoxM1 overexpression promotes epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma. World J. Gastroenterol. 21, 196–213 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aytes, A. et al. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 25, 638–651 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xue, J. et al. Sustained activation of SMAD3/SMAD4 by FOXM1 promotes TGF-β-dependent cancer metastasis. J. Clin. Invest. 124, 564–579 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 6, 345–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  59. Stewart, T. J. & Abrams, S. I. How tumours escape mass destruction. Oncogene 27, 5894–5903 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Loskog, A. et al. Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines. J. Urol. 177, 353–358 (2007).

    Article  PubMed  Google Scholar 

  63. Powles, T. et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515, 558–562 (2014).

    Article  CAS  PubMed  Google Scholar 

  64. Sun, J., Tang, D. N., Fu, T. & Sharma, P. Identification of human regulatory T cells in the setting of T-cell activation and anti-CTLA-4 immunotherapy on the basis of expression of latency-associated peptide. Cancer Discov. 2, 122–130 (2012).

    Article  PubMed  CAS  Google Scholar 

  65. Winerdal, M. E. et al. FOXP3 and survival in urinary bladder cancer. BJU Int. 108, 1672–1678 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. El-Aal, A. A. et al. Immunohistochemical pattern of T lymphocytes population within bilharzial-associated bladder neoplasm microenvironment. Int. J. Immunopathol. Pharmacol. 28, 209–217 (2015).

    Article  PubMed  CAS  Google Scholar 

  67. Phe, V. et al. Forkhead box protein P3 (Foxp3) expression serves as an early chronic inflammation marker of squamous cell differentiation and aggressive pathology of urothelial carcinomas in neurological patients. BJU Int. 115 (Suppl. 6), 28–32 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Sjodahl, G. et al. Infiltration of CD3+ and CD68+ cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors. Urol. Oncol. 32, 791–797 (2014).

    Article  PubMed  Google Scholar 

  69. Shiota, M. et al. Foxo3a suppression of urothelial cancer invasiveness through Twist1, Y-box-binding protein 1, and E-cadherin regulation. Clin. Cancer Res. 16, 5654–5663 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Yu, C. et al. The tumor-suppressor gene Nkx2.8 suppresses bladder cancer proliferation through upregulation of FOXO3a and inhibition of the MEK/ERK signaling pathway. Carcinogenesis 33, 678–686 (2012).

    Article  CAS  PubMed  Google Scholar 

  71. Yang, J. Y. & Hung, M. C. A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin. Cancer Res. 15, 752–757 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Seoane, J., Le, H. V., Shen, L., Anderson, S. A. & Massague, J. Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117, 211–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, T. H. et al. Forkhead box O-class 1 and forkhead box G1 as prognostic markers for bladder cancer. J. Korean Med. Sci. 24, 468–473 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Aoki, M., Jiang, H. & Vogt, P. K. Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc. Natl Acad. Sci. USA 101, 13613–13617 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Kume, T., Deng, K. & Hogan, B. L. Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 127, 1387–1395 (2000).

    CAS  PubMed  Google Scholar 

  76. Bock, M. et al. Identification of ELF3 as an early transcriptional regulator of human urothelium. Dev. Biol. 386, 321–330 (2014).

    Article  PubMed  CAS  Google Scholar 

  77. Hirata, H. et al. MicroRNA-182-5p promotes cell invasion and proliferation by down regulating FOXF2, RECK and MTSS1 genes in human prostate cancer. PLoS ONE 8, e55502 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kundu, S. T. et al. The miR-200 family and the miR-183∼96∼182 cluster target Foxf2 to inhibit invasion and metastasis in lung cancers. Oncogene 35, 173–186 (2016).

    Article  CAS  PubMed  Google Scholar 

  79. Wang, Q. S., Kong, P. Z., Li, X. Q., Yang, F. & Feng, Y. M. FOXF2 deficiency promotes epithelial–mesenchymal transition and metastasis of basal-like breast cancer. Breast Cancer Res. 17, 30 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Zhang, Y. et al. miR-182 promotes cell growth and invasion by targeting forkhead box F2 transcription factor in colorectal cancer. Oncol. Rep. 33, 2592–2598 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Zheng, Y. Z. et al. Decreased mRNA expression of transcription factor forkhead box F2 is an indicator of poor prognosis in patients with resected esophageal squamous cell carcinoma. Mol. Clin. Oncol. 3, 713–719 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Figueroa, J. D. et al. Genome-wide interaction study of smoking and bladder cancer risk. Carcinogenesis 35, 1737–1744 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhang, J. et al. FOXQ1 promotes gastric cancer metastasis through upregulation of Snail. Oncol. Rep. 35, 3607–3613 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. Pei, Y., Wang, P., Liu, H., He, F. & Ming, L. FOXQ1 promotes esophageal cancer proliferation and metastasis by negatively modulating CDH1. Biomed. Pharmacother. 74, 89–94 (2015).

    Article  CAS  PubMed  Google Scholar 

  85. Xiang, X. J. et al. MiR-1271 inhibits cell proliferation, invasion and EMT in gastric cancer by targeting FOXQ1. Cell. Physiol. Biochem. 36, 1382–1394 (2015).

    Article  CAS  PubMed  Google Scholar 

  86. Fan, D. M., Feng, X. S., Qi, P. W. & Chen, Y. W. Forkhead factor FOXQ1 promotes TGF-β1 expression and induces epithelial–mesenchymal transition. Mol. Cell. Biochem. 397, 179–186 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Zhang, H. et al. Forkhead transcription factor Foxq1 promotes epithelial–mesenchymal transition and breast cancer metastasis. Cancer Res. 71, 1292–1301 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhu, Z. et al. Short hairpin RNA targeting FOXQ1 inhibits invasion and metastasis via the reversal of epithelial–mesenchymal transition in bladder cancer. Int. J. Oncol. 42, 1271–1278 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Karni-Schmidt, O. et al. Distinct expression profiles of p63 variants during urothelial development and bladder cancer progression. Am. J. Pathol. 178, 1350–1360 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Signoretti, S. et al. p63 regulates commitment to the prostate cell lineage. Proc. Natl Acad. Sci. USA 102, 11355–11360 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bell, S. M. et al. Kruppel-like factor 5 is required for formation and differentiation of the bladder urothelium. Dev. Biol. 358, 79–90 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gao, Y. et al. Beyond proliferation: KLF5 promotes angiogenesis of bladder cancer through directly regulating VEGFA transcription. Oncotarget 6, 43791–43805 (2015).

    PubMed  PubMed Central  Google Scholar 

  93. Ohnishi, S. et al. Downregulation and growth inhibitory effect of epithelial-type Kruppel-like transcription factor KLF4, but not KLF5, in bladder cancer. Biochem. Biophys. Res. Commun. 308, 251–256 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Varley, C. L. & Southgate, J. Effects of PPAR agonists on proliferation and differentiation in human urothelium. Exp. Toxicol. Pathol. 60, 435–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  95. Biton, A. et al. Independent component analysis uncovers the landscape of the bladder tumor transcriptome and reveals insights into luminal and basal subtypes. Cell Rep. 9, 1235–1245 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Mysorekar, I. U., Mulvey, M. A., Hultgren, S. J. & Gordon, J. I. Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli. J. Biol. Chem. 277, 7412–7419 (2002).

    Article  CAS  PubMed  Google Scholar 

  97. Yu, Z., Mannik, J., Soto, A., Lin, K. K. & Andersen, B. The epidermal differentiation-associated Grainyhead gene Get1/Grhl3 also regulates urothelial differentiation. EMBO J. 28, 1890–1903 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kandimalla, R. et al. Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers. Eur. Urol. 61, 1245–1256 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Drayton, R. M. et al. MicroRNA-99a and 100 mediated upregulation of FOXA1 in bladder cancer. Oncotarget 5, 6375–6386 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We wish to gratefully acknowledge the thoughtful discussions with Dr T. Schell, Dr E. Plimack and Dr S. Holder regarding FOXP3 and the use of immune checkpoint inhibitors for the treatment of bladder cancer. In addition, the authors would like to thank L. Shuman for critically reading and discussing the manuscript. D.J.D. is supported by a Young Investigator Award from the Bladder Cancer Advocacy Network and a National Cancer Institute grant (R00CA172122). J.D.R. is supported by the Ken and Bonney Shockey Fund for Urologic Research.

Author information

Authors and Affiliations

  1. Department of Pathology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, 17033, Pennsylvania, USA

    Hironobu Yamashita, Vasty Osei Amponsa, Joshua I. Warrick, Zongyu Zheng & David J. DeGraff

  2. Department of Urologic Surgery, Vanderbilt University Medical Center, 21st Avenue South, Nashville, 37232, Tennessee, USA

    Peter E. Clark

  3. Department of Surgery, Division of Urology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, 17033, Pennsylvania, USA

    Jay D. Raman & David J. DeGraff

  4. Departments of Pathology and Urology, New York University College of Medicine, New York, 10016, New York, USA

    Xue-Ru Wu

  5. Department of Urology, Columbia University, New York, 10032, New York, USA

    Cathy Mendelsohn

  6. Department of Biochemistry and Molecular Biology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, 17033, Pennsylvania, USA

    David J. DeGraff

Authors
  1. Hironobu Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasty Osei Amponsa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joshua I. Warrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zongyu Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter E. Clark
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jay D. Raman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xue-Ru Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cathy Mendelsohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David J. DeGraff
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, made substantial contributions to discussion of its content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to David J. DeGraff.

Ethics declarations

Competing interests

P.E.C. and D.J.D. have a patent pending for the use of FOXA1 as a prognostic marker in bladder cancer. H.Y., V.O.A., J.I.W., Z.Z., J.D.R., X.-R.W. and C.M. declare no competing interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamashita, H., Amponsa, V., Warrick, J. et al. On a FOX hunt: functions of FOX transcriptional regulators in bladder cancer. Nat Rev Urol 14, 98–106 (2017). https://doi.org/10.1038/nrurol.2016.239

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2016.239

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing