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    NFATc1 promotes prostate tumorigenesis and overcomes PTEN loss-induced senescence

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    Authors
    Manda, K. R.
    Tripathi, P.
    Hsi, A. C.
    Ning, J.
    Ruzinova, M. B.
    Liapis, H.
    Bailey, M.
    Zhang, Hong
    Maher, C. A.
    Humphrey, P. A.
    Andriole, G. L.
    Ding, L.
    You, Z.
    Chen, F.
    Show allShow less
    UMass Chan Affiliations
    Department of Cell and Developmental Biology
    Document Type
    Journal Article
    Publication Date
    2016-06-23
    Keywords
    Cancer Biology
    Cell Biology
    Cellular and Molecular Physiology
    
    Metadata
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    Link to Full Text
    http://dx.doi.org/10.1038/onc.2015.389
    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 IL1beta, 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.
    Source
    Oncogene. 2016 Jun 23;35(25):3282-92. doi: 10.1038/onc.2015.389. Epub 2015 Oct 19. Link to article on publisher's site
    DOI
    10.1038/onc.2015.389
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/26513
    PubMed ID
    26477312
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1038/onc.2015.389
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