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

Nature volume 493, pages 236–240 (2013)Cite this article

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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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Gene Expression Omnibus

Data deposits

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

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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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  1. Gustavo Ayala

    Present address: Present address: Department of Pathology and Laboratory Medicine, University of Texas Health Science Center Medical School, Houston, Texas 77030, USA.,

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Jun Qin, San-Pin Wu, Fangyan Dai, Xin Xie, Chiang-Min Cheng, Xin-Hua Feng, Shaw-Jenq Tsai, Ming-Jer Tsai & Sophia Y. Tsai

  2. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, 77030, Texas, USA

    Chad J. Creighton

  3. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, 77030, Texas, USA

    Fangyan Dai, Xia Lin & Xin-Hua Feng

  4. Department of Pathology and Immunology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Anna Frolov, Gustavo Ayala & Michael M. Ittmann

  5. Department of Physiology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan,

    Shaw-Jenq Tsai

  6. Program in Developmental Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Ming-Jer Tsai & Sophia Y. Tsai

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Contributions

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.

Corresponding authors

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, SP., 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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