COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis

Abstract

Mutations in phosphatase and tensin homologue (PTEN) or genomic alterations in the phosphatidylinositol-3-OH kinase-signalling pathway are the most common genetic alterations reported in human prostate cancer1,2,3,4. However, the precise mechanism underlying how indolent tumours with PTEN alterations acquire metastatic potential remains poorly understood. Recent studies suggest that upregulation of transforming growth factor (TGF)-β signalling triggered by PTEN loss will form a growth barrier as a defence mechanism to constrain prostate cancer progression5, underscoring that TGF-β signalling might represent a pre-invasive checkpoint to prevent PTEN-mediated prostate tumorigenesis. Here we show that COUP transcription factor II (COUP-TFII, also known as NR2F2)6,7,8,9, a member of the nuclear receptor superfamily, serves as a key regulator to inhibit SMAD4-dependent transcription, and consequently overrides the TGF-β-dependent checkpoint for PTEN-null indolent tumours. Overexpression of COUP-TFII in the mouse prostate epithelium cooperates with PTEN deletion to augment malignant progression and produce an aggressive metastasis-prone tumour. The functional counteraction between COUP-TFII and SMAD4 is reinforced by genetically engineered mouse models in which conditional loss of SMAD4 diminishes the inhibitory effects elicited by COUP-TFII ablation. The biological significance of COUP-TFII in prostate carcinogenesis is substantiated by patient sample analysis, in which COUP-TFII expression or activity is tightly correlated with tumour recurrence and disease progression, whereas it is inversely associated with TGF-β signalling. These findings reveal that the destruction of the TGF-β-dependent barrier by COUP-TFII is crucial for the progression of PTEN-mutant prostate cancer into a life-threatening disease, and supports COUP-TFII as a potential drug target for the intervention of metastatic human prostate cancer.

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Figure 1: COUP-TFII is crucial for prostate cancer progression in human and mice.
Figure 2: Prostate-specific overexpression of COUP-TFII promotes tumorigenesis in PTEN mutated mice.
Figure 3: COUP-TFII inhibits TGF-β signalling in prostate cancer cells.
Figure 4: COUP-TFII interacts with SMAD4 to modulate TGF-β signalling.

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Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE33182.

References

  1. 1

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

    CAS  Article  Google Scholar 

  2. 2

    Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, E59 (2003)

    Article  Google Scholar 

  3. 3

    Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003)

    CAS  Article  Google Scholar 

  4. 4

    Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Ding, Z. et al. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature 470, 269–273 (2011)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Pereira, F. A., Qiu, Y., Zhou, G., Tsai, M. J. & Tsai, S. Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 13, 1037–1049 (1999)

    CAS  Article  Google Scholar 

  7. 7

    Takamoto, N. et al. COUP-TFII is essential for radial and anteroposterior patterning of the stomach. Development 132, 2179–2189 (2005)

    CAS  Article  Google Scholar 

  8. 8

    You, L. R. et al. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature 435, 98–104 (2005)

    ADS  CAS  Article  Google Scholar 

  9. 9

    Lin, F. J., Qin, J., Tang, K., Tsai, S. Y. & Tsai, M. J. Coup d’Etat: an orphan takes control. Endocr. Rev. 32, 404–421 (2011)

    CAS  Article  Google Scholar 

  10. 10

    Qin, J., Chen, X., Yu-Lee, L. Y., Tsai, M. J. & Tsai, S. Y. Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling. Cancer Res. 70, 8812–8821 (2010)

    CAS  Article  Google Scholar 

  11. 11

    Qin, J., Chen, X., Xie, X., Tsai, M. J. & Tsai, S. Y. COUP-TFII regulates tumor growth and metastasis by modulating tumor angiogenesis. Proc. Natl Acad. Sci. USA 107, 3687–3692 (2010)

    ADS  CAS  Article  Google Scholar 

  12. 12

    Dhanasekaran, S. M. et al. Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822–826 (2001)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Tomlins, S. A. et al. Integrative molecular concept modeling of prostate cancer progression. Nature Genet. 39, 41–51 (2007)

    CAS  Article  Google Scholar 

  14. 14

    Nagasaki, S. et al. Chicken ovalbumin upstream promoter transcription factor II in human breast carcinoma: possible regulator of lymphangiogenesis via vascular endothelial growth factor-C expression. Cancer Sci. 100, 639–645 (2009)

    CAS  Article  Google Scholar 

  15. 15

    Shin, S. W. et al. Clinical significance of chicken ovalbumin upstream promoter-transcription factor II expression in human colorectal cancer. Oncol. Rep. 21, 101–106 (2009)

    Article  Google Scholar 

  16. 16

    Dyrskjøt, L. et al. Gene expression in the urinary bladder: a common carcinoma in situ gene expression signature exists disregarding histopathological classification. Cancer Res. 64, 4040–4048 (2004)

    Article  Google Scholar 

  17. 17

    Yeh, H. Y. et al. Identifying significant genetic regulatory networks in the prostate cancer from microarray data based on transcription factor analysis and conditional independency. BMC Med. Genomics 2, 70 (2009)

    Article  Google Scholar 

  18. 18

    Jin, C., McKeehan, K. & Wang, F. Transgenic mouse with high Cre recombinase activity in all prostate lobes, seminal vesicle, and ductus deferens. Prostate 57, 160–164 (2003)

    CAS  Article  Google Scholar 

  19. 19

    Padua, D. et al. TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 133, 66–77 (2008)

    CAS  Article  Google Scholar 

  20. 20

    Chen, M. et al. Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell 20, 173–186 (2011)

    CAS  Article  Google Scholar 

  21. 21

    Nakagawa, T. et al. A tissue biomarker panel predicting systemic progression after PSA recurrence post-definitive prostate cancer therapy. PLoS ONE 3, e2318 (2008)

    ADS  Article  Google Scholar 

  22. 22

    Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L. & Robertson, E. J. Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo. Development 131, 3501–3512 (2004)

    CAS  Article  Google Scholar 

  23. 23

    Kruse, S. W. et al. Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor. PLoS Biol. 6, e227 (2008)

    Article  Google Scholar 

  24. 24

    Ayala, G. et al. High levels of phosphorylated form of Akt-1 in prostate cancer and non-neoplastic prostate tissues are strong predictors of biochemical recurrence. Clin. Cancer Res. 10, 6572–6578 (2004)

    CAS  Article  Google Scholar 

  25. 25

    Hodgson, M. C. et al. Decreased expression and androgen regulation of the tumor suppressor gene INPP4B in prostate cancer. Cancer Res. 71, 572–582 (2011)

    CAS  Article  Google Scholar 

  26. 26

    Agoulnik, I. U. et al. Androgens modulate expression of transcription intermediary factor 2, an androgen receptor coactivator whose expression level correlates with early biochemical recurrence in prostate cancer. Cancer Res. 66, 10594–10602 (2006)

    CAS  Article  Google Scholar 

  27. 27

    Wu, S. P., Lee, D. K., Demayo, F. J., Tsai, S. Y. & Tsai, M. J. Generation of ES cells for conditional expression of nuclear receptors and coregulators in vivo. Mol. Endocrinol. 24, 1297–1304 (2010)

    CAS  Article  Google Scholar 

  28. 28

    Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003)

    CAS  Article  Google Scholar 

  29. 29

    Feng, X. H., Liang, Y. Y., Liang, M., Zhai, W. & Lin, X. Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-β-mediated induction of the CDK inhibitor p15Ink4B. Mol. Cell 9, 133–143 (2002)

    CAS  Article  Google Scholar 

  30. 30

    Li, L. et al. The nuclear orphan receptor COUP-TFII plays an essential role in adipogenesis, glucose homeostasis, and energy metabolism. Cell Metab. 9, 77–87 (2009)

    CAS  Article  Google Scholar 

  31. 31

    Park, J. H. et al. Prostatic intraepithelial neoplasia in genetically engineered mice. Am. J. Pathol. 161, 727–735 (2002)

    Article  Google Scholar 

  32. 32

    Creighton, C. J. et al. Integrated analyses of microRNAs demonstrate their widespread influence on gene expression in high-grade serous ovarian carcinoma. PLoS ONE 7, e34546 (2012)

    ADS  CAS  Article  Google Scholar 

  33. 33

    The Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011)

  34. 34

    Creighton, C. J. et al. Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J. Clin. Oncol. 26, 4078–4085 (2008)

    CAS  Article  Google Scholar 

  35. 35

    Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. USA 106, 13820–13825 (2009)

    ADS  CAS  Article  Google Scholar 

  36. 36

    Luo, J. et al. A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835–848 (2009)

    CAS  Article  Google Scholar 

  37. 37

    Glinsky, G. V., Glinskii, A. B., Stephenson, A. J., Hoffman, R. M. & Gerald, W. L. Gene expression profiling predicts clinical outcome of prostate cancer. J. Clin. Invest. 113, 913–923 (2004)

    CAS  Article  Google Scholar 

  38. 38

    Yu, Y. P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004)

    CAS  Article  Google Scholar 

  39. 39

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

    CAS  Article  Google Scholar 

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Acknowledgements

We thank H. Wu for the Ptenflox/flox mice, F. Wang for ARR2PB-Cre (PB-Cre) transgenic mice and E. J. Robertson for the Smad4flox/flox mice. We thank H. K. Graves and L.-Y. Yu-Lee for editorial assistance and S. Elledge for comments. We also thank the Baylor Microarray Core supported by the DERC Center (P30 DK079638) for the microarray analysis. This work was supported by grants from the National Institutes of Health DK62434, DK59820 (S.Y.T. and M.-J.T.), DK45641 (M.-J.T.) and HL76448 (S.Y.T.), and the Dan L. Duncan Cancer Center.

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J.Q., M.-J.T. and S.Y.T. conceived and designed the experimental approach, performed experiments and prepared the manuscript as senior authors. C.J.C. contributed to computational analysis for gene signature analysis and statistical analysis. A.F., G.A. and M.M.I. performed TMA and pathology analyses. S.-P.W. generated COUP-TFIIOE/+ mice. F.D., X.X. and C.-M.C. performed and X.-H.F., X.L. and S.-J.T. supervised a specific subset of experimental design and analysis.

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Correspondence to Ming-Jer Tsai or Sophia Y. Tsai.

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The authors declare no competing financial interests.

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Qin, J., Wu, S., Creighton, C. et al. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature 493, 236–240 (2013). https://doi.org/10.1038/nature11674

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