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.

  • Original Article
  • Published:

FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression

Oncogene volume 35, pages 4335–4344 (2016)Cite this article

Subjects

Abstract

Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2 and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. Chromatin immunoprecipitation sequencing analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not reprograms, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer.

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
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

Accession codes

Accessions

Gene Expression Omnibus

References

  1. Gao N, Zhang J, Rao MA, Case TC, Mirosevich J, Wang Y et al. The role of hepatocyte nuclear factor-3 alpha (Forkhead Box A1) and androgen receptor in transcriptional regulation of prostatic genes. Mol Endocrinol 2003; 17: 1484–1507.

    Article  CAS  Google Scholar 

  2. Lupien M, Eeckhoute J, Meyer CA, Wang Q, Zhang Y, Li W et al. FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 2008; 132: 958–970.

    Article  CAS  Google Scholar 

  3. Jozwik KM, Carroll JS . Pioneer factors in hormone-dependent cancers. Nat Rev Cancer 2012; 12: 381–385.

    Article  CAS  Google Scholar 

  4. Sekiya T, Muthurajan UM, Luger K, Tulin AV, Zaret KS . Nucleosome-binding affinity as a primary determinant of the nuclear mobility of the pioneer transcription factor FoxA. Genes Dev 2009; 23: 804–809.

    Article  CAS  Google Scholar 

  5. Wang D, Garcia-Bassets I, Benner C, Li W, Su X, Zhou Y et al. Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 2011; 474: 390–394.

    Article  CAS  Google Scholar 

  6. Jin HJ, Zhao JC, Wu L, Kim J, Yu J . Cooperativity and equilibrium with FOXA1 define the androgen receptor transcriptional program. Nat Commun 2014; 5: 3972.

    Article  CAS  Google Scholar 

  7. Sahu B, Laakso M, Ovaska K, Mirtti T, Lundin J, Rannikko A et al. Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 2011; 30: 3962–3976.

    Article  CAS  Google Scholar 

  8. Jin HJ, Zhao JC, Ogden I, Bergan RC, Yu J . Androgen receptor-independent function of FoxA1 in prostate cancer metastasis. Cancer Res 2013; 73: 3725–3736.

    Article  CAS  Google Scholar 

  9. Gerhardt J, Montani M, Wild P, Beer M, Huber F, Hermanns T et al. FOXA1 promotes tumor progression in prostate cancer and represents a novel hallmark of castration-resistant prostate cancer. Am J Pathol 2012; 180: 848–861.

    Article  CAS  Google Scholar 

  10. Zhang C, Wang L, Wu D, Chen H, Chen Z, Thomas-Ahner JM et al. Definition of a FoxA1 Cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer. Cancer Res 2011; 71: 6738–6748.

    Article  CAS  Google Scholar 

  11. Wang Q, Li W, Liu XS, Carroll JS, Janne OA, Keeton EK et al. A hierarchical network of transcription factors governs androgen receptor-dependent prostate cancer growth. Mol Cell 2007; 27: 380–392.

    Article  Google Scholar 

  12. Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, Shukla S et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 2013; 19: 1023–1029.

    Article  CAS  Google Scholar 

  13. Pevny L, Simon MC, Robertson E, Klein WH, Tsai SF, D'Agati V et al. Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1. Nature 1991; 349: 257–260.

    Article  CAS  Google Scholar 

  14. Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH . A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J 1997; 16: 3965–3973.

    Article  CAS  Google Scholar 

  15. Yu M, Riva L, Xie H, Schindler Y, Moran TB, Cheng Y et al. Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis. Mol Cell 2009; 36: 682–695.

    Article  CAS  Google Scholar 

  16. Boyes J, Omichinski J, Clark D, Pikaart M, Felsenfeld G . Perturbation of nucleosome structure by the erythroid transcription factor GATA-1. J Mol Biol 1998; 279: 529–544.

    Article  CAS  Google Scholar 

  17. Bossard P, Zaret KS . GATA transcription factors as potentiators of gut endoderm differentiation. Development 1998; 125: 4909–4917.

    CAS  PubMed  Google Scholar 

  18. He B, Lanz RB, Fiskus W, Geng C, Yi P, Hartig SM et al. GATA2 facilitates steroid receptor coactivator recruitment to the androgen receptor complex. Proc Natl Acad Sci USA 2014; 111: 18261–18266.

    Article  CAS  Google Scholar 

  19. Wu D, Sunkel B, Chen Z, Liu X, Ye Z, Li Q et al. Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer. Nucleic Acids Res 2014; 42: 3607–3622.

    Article  CAS  Google Scholar 

  20. Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Barrueco R, Lujambio A, Williams E et al. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell 2015; 27: 223–239.

    Article  CAS  Google Scholar 

  21. Cai C, He HH, Chen S, Coleman I, Wang H, Fang Z et al. Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 2011; 20: 457–471.

    Article  CAS  Google Scholar 

  22. Zhao JC, Yu J, Runkle C, Wu L, Hu M, Wu D et al. Cooperation between Polycomb and androgen receptor during oncogenic transformation. Genome Res 2012; 22: 322–331.

    Article  CAS  Google Scholar 

  23. Wu Q, Dhir R, Wells A . Altered CXCR3 isoform expression regulates prostate cancer cell migration and invasion. Mol Cancer 2012; 11: 3.

    Article  CAS  Google Scholar 

  24. Godoy P, Cadenas C, Hellwig B, Marchan R, Stewart J, Reif R et al. Interferon-inducible guanylate binding protein (GBP2) is associated with better prognosis in breast cancer and indicates an efficient T cell response. Breast Cancer 2014; 21: 491–499.

    Article  Google Scholar 

  25. Andreu-Vieyra C, Lai J, Berman BP, Frenkel B, Jia L, Jones PA et al. Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Mol Cell Biol 2011; 31: 4648–4662.

    Article  CAS  Google Scholar 

  26. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239–243.

    Article  CAS  Google Scholar 

  27. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 2012; 44: 685–689.

    Article  CAS  Google Scholar 

  28. Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell 2010; 17: 443–454.

    Article  CAS  Google Scholar 

  29. Wu L, Runkle C, Jin HJ, Yu J, Li J, Yang X et al. CCN3/NOV gene expression in human prostate cancer is directly suppressed by the androgen receptor. Oncogene 2013; 33: 504–513.

    Article  Google Scholar 

Download references

Acknowledgements

We thank Dr John Crispino (Northwestern University) for critical reading of the manuscript. The project described was supported by the Robert H Lurie Comprehensive Cancer Center (P30CA060553), SPORE in Prostate Cancer (P50CA180995), and the Research Scholar Award RSG-12-085-01 (to JY) from the American Cancer Society. JK was supported in part by the NIH Training Program in Oncogenesis and Developmental Biology (T32CA080621), and YAY was supported in part by the NIH/NCI training grant T32CA009560. Computational analysis was supported by the computational resources and staff contributions provided for the Quest high performance computing facility at Northwestern University which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. Accession Numbers: New high-throughput data generated in this study has been deposited in GEO database under accession number GSE69045.

Author information

Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    J C Zhao, K-W Fong, H-J Jin, Y A Yang, J Kim & J Yu

  2. Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    J Yu

Authors
  1. J C Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K-W Fong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H-J Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y A Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Yu.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, J., Fong, KW., Jin, HJ. et al. FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression. Oncogene 35, 4335–4344 (2016). https://doi.org/10.1038/onc.2015.496

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.496

This article is cited by

Search

Advanced search

Quick links