p68/DdX5 supports β-Catenin & RNAP II during androgen receptor mediated transcription in prostate cancer

Emma L. Clark, Christiana Hadjimichael, Richard Temperley, Amy Barnard, Frances V. Fuller-Pace, Craig N. Robson (Lead / Corresponding author)

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    Abstract

    The DEAD box RNA helicase p68 (Ddx5) is an important androgen receptor (AR) transcriptional co-activator in prostate cancer (PCa) and is over-expressed in late stage disease. beta-Catenin is a multifunctional protein with important structural and signalling functions which is up-regulated in PCa and similar to p68, interacts with the AR to co-activate expression of AR target genes. Importantly, p68 forms complexes with nuclear beta-Catenin and promotes gene transcription in colon cancer indicating a functional interplay between these two proteins in cancer progression. In this study, we explore the relationship of p68 and beta-Catenin in PCa to assess their potential co-operation in AR-dependent gene expression, which may be of importance in the development of castrate resistant prostate cancer (CRPCa). We use immunoprecipitation to demonstrate a novel interaction between p68 and beta-Catenin in the nucleus of PCa cells, which is androgen dependent in LNCaP cells but androgen independent in a hormone refractory derivative of the same cell line (representative of the CRPCa disease type). Enhanced AR activity is seen in androgen-dependent luciferase reporter assays upon transient co-transfection of p68 and beta-Catenin as an additive effect, and p68-depleted Chromatin-Immunoprecipitation (ChIP) showed a decrease in the recruitment of the AR and beta-Catenin to androgen responsive promoter regions. In addition, we found p68 immunoprecipitated with the processive and non-processive form of RNA polymerase II (RNAP II) and show p68 recruited to elongating regions of the AR mediated PSA gene, suggesting a role for p68 in facilitating RNAP II transcription of AR mediated genes. These results suggest p68 is important in facilitating beta-Catenin and AR transcriptional activity in PCa cells.

    Original languageEnglish
    Article numbere54150
    Number of pages10
    JournalPLoS ONE
    Volume8
    Issue number1
    DOIs
    Publication statusPublished - 17 Jan 2013

    Keywords

    • COLON-CANCER
    • WNT/BETA-CATENIN
    • GROWTH
    • WNT SIGNALING PATHWAYS
    • COACTIVATOR
    • HISTONE DEACETYLASE-1
    • EXPRESSION
    • MULTIFUNCTIONAL PROTEINS
    • NUCLEAR TRANSLOCATION
    • HELICASE P68

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