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NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence

Oncogene volume 35, pages 3282–3292 (2016)Cite this article

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Abstract

Despite recent insights into prostate cancer (PCa)-associated genetic changes, full understanding of prostate tumorigenesis remains elusive owing to complexity of interactions among various cell types and soluble factors present in prostate tissue. We found the upregulation of nuclear factor of activated T cells c1 (NFATc1) in human PCa and cultured PCa cells, but not in normal prostates and non-tumorigenic prostate cells. To understand the role of NFATc1 in prostate tumorigenesis in situ, we temporally and spatially controlled the activation of NFATc1 in mouse prostate and showed that such activation resulted in prostatic adenocarcinoma with features similar to those seen in human PCa. Our results indicate that the activation of a single transcription factor, NFATc1 in prostatic luminal epithelium to PCa can affect expression of diverse factors in both cells harboring the genetic changes and in neighboring cells through microenvironmental alterations. In addition to the activation of oncogenes c-MYC and STAT3 in tumor cells, a number of cytokines and growth factors, such as IL1β, IL6 and SPP1 (osteopontin, a key biomarker for PCa), were upregulated in NFATc1-induced PCa, establishing a tumorigenic microenvironment involving both NFATc1 positive and negative cells for prostate tumorigenesis. To further characterize interactions between genes involved in prostate tumorigenesis, we generated mice with both NFATc1 activation and Pten inactivation in prostate. We showed that NFATc1 activation led to acceleration of Pten null-driven prostate tumorigenesis by overcoming the PTEN loss-induced cellular senescence through inhibition of p21 activation. This study provides direct in vivo evidence of an oncogenic role of NFATc1 in prostate tumorigenesis and reveals multiple functions of NFATc1 in activating oncogenes, in inducing proinflammatory cytokines, in oncogene addiction, and in overcoming cellular senescence, which suggests calcineurin-NFAT signaling as a potential target in preventing PCa.

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Acknowledgements

We thank Drs Gerald Crabtree and Minggui Pan for providing the TetO-NFATc1Nuc mice. FC is supported in part by grants from DoD (PC130118) and NIH (DK087960). ZY is supported in part by NIH R01CA174714. LD is supported in part by grants from NIH (R01CA180006, R01CA178383 and U01HG006517).

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Authors and Affiliations

  1. Department of Medicine, Washington University, School of Medicine, St Louis, MO, USA

    K R Manda, J Ning, C A Maher, L Ding & F Chen

  2. Department of Pathology and Immunology, Washington University, St Louis, MO, USA

    P Tripathi, M B Ruzinova & H Liapis

  3. The Genome Institute, Washington University, St Louis, MO, USA

    A C Hsi, J Ning, M Bailey, C A Maher & L Ding

  4. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA

    H Zhang

  5. Siteman Cancer Center, Washington University, St Louis, MO, USA

    C A Maher, G L Andriole, L Ding & F Chen

  6. Department of Pathology, Yale University, New Haven, CT, USA

    P A Humphrey

  7. Department of Surgery, Washington University, St Louis, MO, USA

    G L Andriole

  8. Department of Structural and Cellular Biology, Tulane University, New Orleans, LA, USA

    Z You

  9. Department of Cell Biology and Physiology, Washington University, St Louis, MO, USA

    F Chen

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Correspondence to F Chen.

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Manda, K., Tripathi, P., Hsi, A. et al. NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence. Oncogene 35, 3282–3292 (2016). https://doi.org/10.1038/onc.2015.389

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  • DOI: https://doi.org/10.1038/onc.2015.389

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