Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model

J. Ai, L. E. Pascal, K. J. O'Malley, J. A. Dar, S. Isharwal, Z. Qiao, B. Ren, L. H. Rigatti, R. Dhir, W. Xiao, J. B. Nelson, Z. Wang

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    18 Scopus citations

    Abstract

    Multiple genetic alterations are associated with prostate carcinogenesis. Tumor-suppressor genes phosphatase and tensin homolog deleted on chromosome 10 (Pten) and androgen upregulated gene 19 (U19), which encodes ELL-associated factor 2 (EAF2), are frequently inactivated or downregulated in advanced prostate cancers. Previous studies showed that EAF2 knockout caused tumors in multiple organs and prostatic intraepithelial neoplasia (PIN) in mice. However, EAF2-knockout mice did not develop prostate cancer even at 2 years of age. To further define the roles of EAF2 in prostate carcinogenesis, we crossed the Pten+/- and EAF2+/- mice in the C57/BL6 background to generate EAF2-/-Pten+/-, Pten+/-, EAF2-/- and wild-type mice. The prostates from virgin male mice with the above four genotypes were analyzed at 7 weeks, 19 weeks and 12 months of age. Concomitant loss of EAF2 function and inactivation of one Pten allele induced spontaneous prostate cancer in 33% of the mice. Prostatic tissues from intact EAF2-/- Pten+/- mice exhibited higher levels of phospho-Akt, -p44/42 and microvessel density. Moreover, phospho-Akt remained high after castration. Consistently, there was a synergistic increase in prostate epithelial proliferation in both intact and castrated EAF2-/-Pten+/- mice. Using laser-capture microdissection coupled with real-time reverse transcription-PCR, we confirmed that co-downregulation of EAF2 and Pten occurred in >50% clinical prostate cancer specimens with Gleason scores of 8-9 (n=11), which is associated with poor prognosis. The above findings together demonstrated synergistic functional interactions and clinical relevance of concurrent EAF2 and Pten downregulation in prostate carcinogenesis.

    Original languageEnglish (US)
    Pages (from-to)2286-2294
    Number of pages9
    JournalOncogene
    Volume33
    Issue number18
    DOIs
    StatePublished - May 1 2014

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    Keywords

    • EAF2/U19
    • Knockout
    • Prostate cancer
    • Pten

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Cancer Research

    Cite this

    Ai, J., Pascal, L. E., O'Malley, K. J., Dar, J. A., Isharwal, S., Qiao, Z., Ren, B., Rigatti, L. H., Dhir, R., Xiao, W., Nelson, J. B., & Wang, Z. (2014). Concomitant loss of EAF2/U19 and Pten synergistically promotes prostate carcinogenesis in the mouse model. Oncogene, 33(18), 2286-2294. https://doi.org/10.1038/onc.2013.190