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The role of GATA2 in lethal prostate cancer aggressiveness

Nature Reviews Urology volume 14, pages 38–48 (2017)Cite this article

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Key Points

  • Endothelial transcription factor GATA-2 (GATA2) is a pioneer, master-regulator, transcription factor that binds DNA regions of closed chromatin, causing opening and facilitating subsequent hierarchical binding of other regulators that activate transcription

  • GATA2 is crucial for the development of the genitourinary system and might be a lineage marker of mouse and human prostate tissue

  • GATA2 drives androgen-responsive gene expression and contributes to prostate cancer metastasis by increasing tumour cell motility and invasiveness in early stages of the disease, through its pioneer transcription factor function

  • GATA2 is important in prostate cancer progression to an androgen-refractory state and regulates an androgen-independent signalling network in late stages of the disease

  • Preclinical experimental data have demonstrated the utility of inhibiting GATA2 through targeting its upstream regulators, post-translational modifications, and downstream effectors

  • Integrating GATA2 inhibition into the therapeutic landscape of prostate cancer will require the development of precise predictive assays and identification of the most effective therapeutic combination

Abstract

Advanced prostate cancer is a classic example of the intractability and consequent lethality that characterizes metastatic carcinomas. Novel treatments have improved the survival of men with prostate cancer; however, advanced prostate cancer invariably becomes resistant to these therapies and ultimately progresses to a lethal metastatic stage. Consequently, detailed knowledge of the molecular mechanisms that control prostate cancer cell survival and progression towards this lethal stage of disease will benefit the development of new therapeutics. The transcription factor endothelial transcription factor GATA-2 (GATA2) has been reported to have a key role in driving prostate cancer aggressiveness. In addition to being a pioneer transcription factor that increases androgen receptor (AR) binding and activity, GATA2 regulates a core subset of clinically relevant genes in an AR-independent manner. Functionally, GATA2 overexpression in prostate cancer increases cellular motility and invasiveness, proliferation, tumorigenicity, and resistance to standard therapies. Thus, GATA2 has a multifaceted function in prostate cancer aggressiveness and is a highly attractive target in the development of novel treatments against lethal prostate cancer.

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Figure 1: The pioneer endothelial transcription factor GATA-2 (GATA2).
Figure 2: Endothelial transcription factor GATA-2 (GATA2) regulates lethal prostate cancer aggressiveness.
Figure 3: Different strategies for targeting endothelial transcription factor GATA-2 (GATA2) in prostate cancer.

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Change history

  • 25 November 2016

    In the original version of this article the acknowledgements section was omitted. This has been corrected in the print and online versions of the manuscript.

References

  1. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

    PubMed  Google Scholar 

  2. Pound, C. R. et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281, 1591–1597 (1999).

    CAS  PubMed  Google Scholar 

  3. Klotz, L. et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J. Clin. Oncol. 33, 272–277 (2015).

    PubMed  Google Scholar 

  4. Seidenfeld, J. et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann. Intern. Med. 132, 566–577 (2000).

    CAS  PubMed  Google Scholar 

  5. Hellerstedt, B. A. & Pienta, K. J. The current state of hormonal therapy for prostate cancer. CA Cancer J. Clin. 52, 154–179 (2002).

    PubMed  Google Scholar 

  6. Petrylak, D. P. et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351, 1513–1520 (2004).

    CAS  PubMed  Google Scholar 

  7. Tannock, I. F. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

    CAS  PubMed  Google Scholar 

  8. de Bono, J. S. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376, 1147–1154 (2010).

    CAS  PubMed  Google Scholar 

  9. Sweeney, C. J. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N. Engl. J. Med. 373, 737–746 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. James, N. D. et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 387, 1163–1177 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364, 1995–2005 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Beer, T. M. et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371, 424–433 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. Ryan, C. J. et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368, 138–148 (2013).

    CAS  PubMed  Google Scholar 

  14. Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367, 1187–1197 (2012).

    CAS  PubMed  Google Scholar 

  15. Parker, C. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369, 213–223 (2013).

    CAS  PubMed  Google Scholar 

  16. Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    CAS  PubMed  Google Scholar 

  17. Huggins, C. & Hodges, C. V. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1, 293–297 (1941).

    CAS  Google Scholar 

  18. Huggins, C., Stevens, R. E. & Hodges, C. V. Studies on prostate cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch. Surg. 43, 209–223 (1941).

    CAS  Google Scholar 

  19. Knudsen, K. E. & Penning, T. M. Partners in crime: deregulation of AR activity and androgen synthesis in prostate cancer. Trends Endocrinol. Metab. 21, 315–324 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zong, Y. & Goldstein, A. S. Adaptation or selection — mechanisms of castration-resistant prostate cancer. Nat. Rev. Urol. 10, 90–98 (2013).

    CAS  PubMed  Google Scholar 

  21. Armstrong, C. M. & Gao, A. C. Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies. Am. J. Clin. Exp. Urol. 3, 64–76 (2015).

    PubMed  PubMed Central  Google Scholar 

  22. Bresnick, E. H., Lee, H. Y., Fujiwara, T., Johnson, K. D. & Keles, S. GATA switches as developmental drivers. J. Biol. Chem. 285, 31087–31093 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Burch, J. B. Regulation of GATA gene expression during vertebrate development. Semin. Cell Dev. Biol. 16, 71–81 (2005).

    CAS  PubMed  Google Scholar 

  24. Vicente, C., Conchillo, A., Garcia-Sanchez, M. A. & Odero, M. D. The role of the GATA2 transcription factor in normal and malignant hematopoiesis. Crit. Rev. Oncol. Hematol. 82, 1–17 (2012).

    PubMed  Google Scholar 

  25. Zheng, R. & Blobel, G. A. GATA transcription factors and cancer. Genes Cancer 1, 1178–1188 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Evans, T., Reitman, M. & Felsenfeld, G. An erythrocyte-specific DNA-binding factor recognizes a regulatory sequence common to all chicken globin genes. Proc. Natl Acad. Sci. USA 85, 5976–5980 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Weiss, M. J. & Orkin, S. H. GATA transcription factors: key regulators of hematopoiesis. Exp. Hematol. 23, 99–107 (1995).

    CAS  PubMed  Google Scholar 

  28. Nemer, G. & Nemer, M. Transcriptional activation of BMP-4 and regulation of mammalian organogenesis by GATA-4 and -6. Dev. Biol. 254, 131–148 (2003).

    CAS  PubMed  Google Scholar 

  29. Kaplan, T. et al. Quantitative models of the mechanisms that control genome-wide patterns of transcription factor binding during early Drosophila development. PLoS Genet. 7, e1001290 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwafuchi-Doi, M. & Zaret, K. S. Pioneer transcription factors in cell reprogramming. Genes Dev. 28, 2679–2692 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).

    CAS  PubMed  Google Scholar 

  33. Bossard, P. & Zaret, K. S. GATA transcription factors as potentiators of gut endoderm differentiation. Development 125, 4909–4917 (1998).

    CAS  PubMed  Google Scholar 

  34. Tsai, F. Y. et al. An early haematopoietic defect in mice lacking the transcription factor GATA-2. Nature 371, 221–226 (1994).

    CAS  PubMed  Google Scholar 

  35. Tsai, F. Y. & Orkin, S. H. Transcription factor GATA-2 is required for proliferation/survival of early hematopoietic cells and mast cell formation, but not for erythroid and myeloid terminal differentiation. Blood 89, 3636–3643 (1997).

    CAS  PubMed  Google Scholar 

  36. Kumano, K. et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity 18, 699–711 (2003).

    CAS  PubMed  Google Scholar 

  37. Robert-Moreno, A., Espinosa, L., de la Pompa, J. L. & Bigas, A. RBPjκ-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development 132, 1117–1126 (2005).

    CAS  PubMed  Google Scholar 

  38. Fujiwara, Y., Browne, C. P., Cunniff, K., Goff, S. C. & Orkin, S. H. Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc. Natl Acad. Sci. USA 93, 12355–12358 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Orlic, D., Anderson, S., Biesecker, L. G., Sorrentino, B. P. & Bodine, D. M. Pluripotent hematopoietic stem cells contain high levels of mRNA for c-kit, GATA-2, 45 NF-E2, and c-myb and low levels or no mRNA for c-fms and the receptors for granulocyte colony-stimulating factor and interleukins 5 and 7. Proc. Natl Acad. Sci. USA 92, 4601–4605 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Minegishi, N. et al. Alternative promoters regulate transcription of the mouse GATA-2 gene. J. Biol. Chem. 273, 3625–3634 (1998).

    CAS  PubMed  Google Scholar 

  41. Ling, K. W. et al. GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells. J. Exp. Med. 200, 871–882 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Lugus, J. J. et al. GATA2 functions at multiple steps in hemangioblast development and differentiation. Development 134, 393–405 (2007).

    CAS  PubMed  Google Scholar 

  43. Xiong, J. W. Molecular and developmental biology of the hemangioblast. Dev. Dyn. 237, 1218–1231 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Nishikawa, S. I. A complex linkage in the developmental pathway of endothelial and hematopoietic cells. Curr. Opin. Cell Biol. 13, 673–678 (2001).

    CAS  PubMed  Google Scholar 

  45. Gumina, R. J., Kirschbaum, N. E., Piotrowski, K. & Newman, P. J. Characterization of the human platelet/endothelial cell adhesion molecule-1 promoter: identification of a GATA-2 binding element required for optimal transcriptional activity. Blood 89, 1260–1269 (1997).

    CAS  PubMed  Google Scholar 

  46. Lee, M. E., Temizer, D. H., Clifford, J. A. & Quertermous, T. Cloning of the GATA-binding protein that regulates endothelin-1 gene expression in endothelial cells. J. Biol. Chem. 266, 16188–16192 (1991).

    CAS  PubMed  Google Scholar 

  47. Kappel, A. et al. Role of SCL/Tal-1, GATA, and ets transcription factor binding sites for the regulation of Flk-1 expression during murine vascular development. Blood 96, 3078–3085 (2000).

    CAS  PubMed  Google Scholar 

  48. Coma, S. et al. GATA2 and Lmo2 control angiogenesis and lymphangiogenesis via direct transcriptional regulation of neuropilin-2. Angiogenesis 16, 939–952 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhou, Y. et al. Rescue of the embryonic lethal hematopoietic defect reveals a critical role for GATA-2 in urogenital development. EMBO J. 17, 6689–6700 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Khandekar, M., Suzuki, N., Lewton, J., Yamamoto, M. & Engel, J. D. Multiple, distant Gata2 enhancers specify temporally and tissue-specific patterning in the developing urogenital system. Mol. Cell. Biol. 24, 10263–10276 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Perez-Stable, C. M., Pozas, A. & Roos, B. A. A role for GATA transcription factors in the androgen regulation of the prostate-specific antigen gene enhancer. Mol. Cell. Endocrinol. 167, 43–53 (2000).

    CAS  PubMed  Google Scholar 

  52. Spinner, M. A. et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood 123, 809–821 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mansour, S. et al. Emberger syndrome-primary lymphedema with myelodysplasia: report of seven new cases. Am. J. Med. Genet. A 152A, 2287–2296 (2010).

    PubMed  Google Scholar 

  54. Ostergaard, P. et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat. Genet. 43, 929–931 (2011).

    CAS  PubMed  Google Scholar 

  55. Hsu, A. P. et al. Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome. Blood 118, 2653–2655 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Dickinson, R. E. et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 118, 2656–2658 (2011).

    CAS  PubMed  Google Scholar 

  57. Wang, Q. et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol. Cell 27, 380–392 (2007).

    PubMed  PubMed Central  Google Scholar 

  58. Wu, D. et al. Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res. 42, 3607–3622 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Vidal, S. J. et al. A targetable GATA2–IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell 27, 223–239 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Watahiki, A. et al. MicroRNAs associated with metastatic prostate cancer. PLoS ONE 6, e24950 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chiang, Y. T. et al. GATA2 as a potential metastasis-driving gene in prostate cancer. Oncotarget 5, 451–461 (2014).

    PubMed  PubMed Central  Google Scholar 

  62. He, B. et al. GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex. Proc. Natl Acad. Sci. USA 111, 18261–18266 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bohm, M., Locke, W. J., Sutherland, R. L., Kench, J. G. & Henshall, S. M. A role for GATA-2 in transition to an aggressive phenotype in prostate cancer through modulation of key androgen-regulated genes. Oncogene 28, 3847–3856 (2009).

    CAS  PubMed  Google Scholar 

  64. Cleutjens, K. B. et al. An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Mol. Endocrinol. 11, 148–161 (1997).

    CAS  PubMed  Google Scholar 

  65. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    CAS  PubMed  Google Scholar 

  66. Henshall, S. M. et al. Zinc-alpha2-glycoprotein expression as a predictor of metastatic prostate cancer following radical prostatectomy. J. Natl Cancer Inst. 98, 1420–1424 (2006).

    CAS  PubMed  Google Scholar 

  67. Wang, Q. et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138, 245–256 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jin, Q. et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011).

    CAS  PubMed  Google Scholar 

  69. Zhao, J. C. et al. FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression. Oncogene 35, 4335–4344 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Karantanos, T., Corn, P. G. & Thompson, T. C. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 32, 5501–5511 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Harris, W. P., Mostaghel, E. A., Nelson, P. S. & Montgomery, B. Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat. Clin. Pract. Urol. 6, 76–85 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Pienta, K. J. & Bradley, D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin. Cancer Res. 12, 1665–1671 (2006).

    CAS  PubMed  Google Scholar 

  73. Cookson, M. S. et al. Castration-resistant prostate cancer: AUA guideline. J. Urol. 190, 429–438 (2013).

    PubMed  Google Scholar 

  74. Debes, J. D. & Tindall, D. J. Mechanisms of androgen-refractory prostate cancer. N. Engl. J. Med. 351, 1488–1490 (2004).

    CAS  PubMed  Google Scholar 

  75. Dutt, S. S. & Gao, A. C. Molecular mechanisms of castration-resistant prostate cancer progression. Future Oncol. 5, 1403–1413 (2009).

    CAS  PubMed  Google Scholar 

  76. Hendriksen, P. J. et al. Evolution of the androgen receptor pathway during progression of prostate cancer. Cancer Res. 66, 5012–5020 (2006).

    CAS  PubMed  Google Scholar 

  77. Cai, C. et al. Lysine-specific demethylase 1 has dual functions as a major regulator of androgen receptor transcriptional activity. Cell Rep. 9, 1618–1627 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen, Z. et al. Phospho-MED1-enhanced UBE2C locus looping drives castration-resistant prostate cancer growth. EMBO J. 30, 2405–2419 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bishr, M. & Saad, F. Overview of the latest treatments for castration-resistant prostate cancer. Nat. Rev. Urol. 10, 522–528 (2013).

    CAS  PubMed  Google Scholar 

  80. Mulholland, D. J. et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19, 792–804 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kumar, M. S. et al. The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149, 642–655 (2012).

    CAS  PubMed  Google Scholar 

  82. Hoelder, S., Clarke, P. A. & Workman, P. Discovery of small molecule cancer drugs: successes, challenges and opportunities. Mol. Oncol. 6, 155–176 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lazo, J. S. & Sharlow, E. R. Drugging undruggable molecular cancer targets. Annu. Rev. Pharmacol. Toxicol. 56, 23–40 (2016).

    CAS  PubMed  Google Scholar 

  84. Zeuner, A. et al. The Notch2–Jagged1 interaction mediates stem cell factor signaling in erythropoiesis. Cell Death Differ. 18, 371–380 (2011).

    CAS  PubMed  Google Scholar 

  85. Catelain, C. et al. The Notch Delta-4 ligand helps to maintain the quiescence and the short-term reconstitutive potential of haematopoietic progenitor cells through activation of a key gene network. Stem Cell Res. 13, 431–441 (2014).

    CAS  PubMed  Google Scholar 

  86. Guiu, J. et al. Hes repressors are essential regulators of hematopoietic stem cell development downstream of Notch signaling. J. Exp. Med. 210, 71–84 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. de Pooter, R. F. et al. Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors. J. Immunol. 176, 5267–5275 (2006).

    CAS  PubMed  Google Scholar 

  88. Kumano, K. et al. Notch1 inhibits differentiation of hematopoietic cells by sustaining GATA-2 expression. Blood 98, 3283–3289 (2001).

    CAS  PubMed  Google Scholar 

  89. Robert-Moreno, A. et al. Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J. 27, 1886–1895 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Flores, A. N., McDermott, N., Meunier, A. & Marignol, L. NUMB inhibition of NOTCH signalling as a therapeutic target in prostate cancer. Nat. Rev. Urol. 11, 499–507 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Su, Q. & Xin, L. Notch signaling in prostate cancer: refining a therapeutic opportunity. Histol. Histopathol. 31, 149–157 (2016).

    CAS  PubMed  Google Scholar 

  92. Marignol, L., Rivera-Figueroa, K., Lynch, T. & Hollywood, D. Hypoxia, notch signalling, and prostate cancer. Nat. Rev. Urol. 10, 405–413 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Domingo-Domenech, J. et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 22, 373–388 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Bertrand, F. E., McCubrey, J. A., Angus, C. W., Nutter, J. M. & Sigounas, G. NOTCH and PTEN in prostate cancer. Adv. Biol. Regul. 56, 51–65 (2014).

    CAS  PubMed  Google Scholar 

  95. Yuan, X. et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 369, 20–27 (2015).

    CAS  PubMed  Google Scholar 

  96. Espinoza, I. & Miele, L. Notch inhibitors for cancer treatment. Pharmacol. Ther. 139, 95–110 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Taoudi, S. et al. ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. Genes Dev. 25, 251–262 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lulli, V. et al. Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation. Cell Death Differ. 13, 1064–1074 (2006).

    CAS  PubMed  Google Scholar 

  99. Craven, S. E. et al. Gata2 specifies serotonergic neurons downstream of sonic hedgehog. Development 131, 1165–1173 (2004).

    CAS  PubMed  Google Scholar 

  100. Suh, J. M. et al. Hedgehog signaling plays a conserved role in inhibiting fat formation. Cell Metab. 3, 25–34 (2006).

    CAS  PubMed  Google Scholar 

  101. Treier, M. et al. Hedgehog signaling is required for pituitary gland development. Development 128, 377–386 (2001).

    CAS  PubMed  Google Scholar 

  102. Dalgin, G. et al. GATA-2 functions downstream of BMPs and CaM KIV in ectodermal cells during primitive hematopoiesis. Dev. Biol. 310, 454–469 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Goldman, O. et al. A boost of BMP4 accelerates the commitment of human embryonic stem cells to the endothelial lineage. Stem Cells 27, 1750–1759 (2009).

    CAS  PubMed  Google Scholar 

  104. Maguer-Satta, V. et al. Regulation of human erythropoiesis by activin A, BMP2, and BMP4, members of the TGFβ family. Exp. Cell Res. 282, 110–120 (2003).

    CAS  PubMed  Google Scholar 

  105. Adamo, P. & Ladomery, M. R. The oncogene ERG: a key factor in prostate cancer. Oncogene 35, 403–414 (2016).

    CAS  PubMed  Google Scholar 

  106. Gonnissen, A., Isebaert, S. & Haustermans, K. Hedgehog signaling in prostate cancer and its therapeutic implication. Int. J. Mol. Sci. 14, 13979–14007 (2013).

    PubMed  PubMed Central  Google Scholar 

  107. Tu, W. H. et al. The loss of TGF-β signaling promotes prostate cancer metastasis. Neoplasia 5, 267–277 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hayakawa, F. et al. Functional regulation of GATA-2 by acetylation. J. Leukoc. Biol. 75, 529–540 (2004).

    CAS  PubMed  Google Scholar 

  109. Ozawa, Y. et al. Histone deacetylase 3 associates with and represses the transcription factor GATA-2. Blood 98, 2116–2123 (2001).

    CAS  PubMed  Google Scholar 

  110. Heemers, H. V., Debes, J. D. & Tindall, D. J. The role of the transcriptional coactivator p300 in prostate cancer progression. Adv. Exp. Med. Biol. 617, 535–540 (2008).

    PubMed  PubMed Central  Google Scholar 

  111. Heemers, H. V. et al. Androgen deprivation increases p300 expression in prostate cancer cells. Cancer Res. 67, 3422–3430 (2007).

    CAS  PubMed  Google Scholar 

  112. Shah, S., Prasad, S. & Knudsen, K. E. Targeting pioneering factor and hormone receptor cooperative pathways to suppress tumor progression. Cancer Res. 72, 1248–1259 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ide, H. et al. Combined inhibitory effects of soy isoflavones and curcumin on the production of prostate-specific antigen. Prostate 70, 1127–1133 (2010).

    CAS  PubMed  Google Scholar 

  114. Thomas, R., Williams, M., Sharma, H., Chaudry, A. & Bellamy, P. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer — the U.K. NCRN Pomi-T study. Prostate Cancer Prostat. Dis. 17, 180–186 (2014).

    CAS  Google Scholar 

  115. Paller, C. J. et al. A phase I study of muscadine grape skin extract in men with biochemically recurrent prostate cancer: safety, tolerability, and dose determination. Prostate 75, 1518–1525 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Mahammedi, H. et al. The new combination docetaxel, prednisone and curcumin in patients with castration-resistant prostate cancer: a pilot phase II study. Oncology 90, 69–78 (2016).

    CAS  PubMed  Google Scholar 

  117. Deguchi, A. Curcumin targets in inflammation and cancer. Endocr. Metab. Immune Disord. Drug Targets 15, 88–96 (2015).

    CAS  PubMed  Google Scholar 

  118. Gupta, S. C. et al. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch. Biochem. Biophys. 559, 91–99 (2014).

    CAS  PubMed  Google Scholar 

  119. Vallianou, N. G., Evangelopoulos, A., Schizas, N. & Kazazis, C. Potential anticancer properties and mechanisms of action of curcumin. Anticancer Res. 35, 645–651 (2015).

    CAS  PubMed  Google Scholar 

  120. Imagawa, S. et al. A GATA-specific inhibitor (K-7174) rescues anemia induced by IL-1β, TNF-α, or L-NMMA. FASEB J. 17, 1742–1744 (2003).

    CAS  PubMed  Google Scholar 

  121. Kikuchi, J. et al. Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding. PLoS ONE 8, e60649 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Minegishi, N., Suzuki, N., Kawatani, Y., Shimizu, R. & Yamamoto, M. Rapid turnover of GATA-2 via ubiquitin-proteasome protein degradation pathway. Genes Cells 10, 693–704 (2005).

    CAS  PubMed  Google Scholar 

  123. Ahn, E. E. et al. SON protein regulates GATA-2 through transcriptional control of the microRNA 23a∼27a∼24–22 cluster. J. Biol. Chem. 288, 5381–5388 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Towatari, M. et al. Regulation of GATA-2 phosphorylation by mitogen-activated protein kinase and interleukin-3. J. Biol. Chem. 270, 4101–4107 (1995).

    CAS  PubMed  Google Scholar 

  125. Menghini, R. et al. Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis. Circulation 111, 1946–1953 (2005).

    CAS  PubMed  Google Scholar 

  126. Katsumura, K. R., Yang, C., Boyer, M. E., Li, L. & Bresnick, E. H. Molecular basis of crosstalk between oncogenic Ras and the master regulator of hematopoiesis GATA-2. EMBO Rep. 15, 938–947 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Baumgartner, C. & Baccarini, M. p38 links RAS to GATA2. EMBO Rep. 15, 912–913 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11–22 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Grasso, C. S. et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 487, 239–243 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Cellot, S. et al. RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity. Blood 122, 1545–1555 (2013).

    CAS  PubMed  Google Scholar 

  132. Celton, M. et al. Epigenetic regulation of GATA2 and its impact on normal karyotype acute myeloid leukemia. Leukemia 28, 1617–1626 (2014).

    CAS  PubMed  Google Scholar 

  133. Dmitriev, A. A. et al. Identification of novel epigenetic markers of prostate cancer by NotI-microarray analysis. Dis. Markers 2015, 241301 (2015).

    PubMed  PubMed Central  Google Scholar 

  134. Estey, E. H. Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia 27, 1803–1812 (2013).

    CAS  PubMed  Google Scholar 

  135. Moriguchi, T. & Yamamoto, M. A regulatory network governing Gata1 and Gata2 gene transcription orchestrates erythroid lineage differentiation. Int. J. Hematol. 100, 417–424 (2014).

    CAS  PubMed  Google Scholar 

  136. Bresnick, E. H., Katsumura, K. R., Lee, H. Y., Johnson, K. D. & Perkins, A. S. Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies. Nucleic Acids Res. 40, 5819–5831 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Livingstone, C. IGF2 and cancer. Endocr. Relat. Cancer 20, R321–R339 (2013).

    CAS  PubMed  Google Scholar 

  138. Mulvihill, M. J. et al. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med. Chem. 1, 1153–1171 (2009).

    CAS  PubMed  Google Scholar 

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Acknowledgements

V.R.-B. receives funding from the U.S. Department of Health & Human Services, NIH, National Cancer Institute grant number 1 K22 CA207458-01 and J.D.-D. receives funding from U.S. Department of Health & Human Services, NIH, National Cancer Institute grant number 1 R01 CA207311-01.

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  1. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Veronica Rodriguez-Bravo, Marc Carceles-Cordon, Carlos Cordon-Cardo & Josep Domingo-Domenech

  2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Veronica Rodriguez-Bravo & Yujin Hoshida

  3. Department of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Matthew D. Galsky

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  1. Veronica Rodriguez-Bravo
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Correspondence to Josep Domingo-Domenech.

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Rodriguez-Bravo, V., Carceles-Cordon, M., Hoshida, Y. et al. The role of GATA2 in lethal prostate cancer aggressiveness. Nat Rev Urol 14, 38–48 (2017). https://doi.org/10.1038/nrurol.2016.225

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