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Publication:

The RNA helicase p68 is a novel androgen receptor coactivator involved in splicing and is overexpressed in prostate cancer (2008)

Author(s): Clark EL, Coulson AC, Dalgliesh C, Rajan P, Nicol SM, Fleming S, Heer R, Gaughan L, Leung HY, Elliott DJ, Fuller-Pace FV, Robson CN

    Abstract: The androgen receptor (AR) is a member of the nuclear steroid hormone receptor family and is thought to play an important role in the development of both androgen-dependent and androgen-independent prostatic malignancy. Elucidating roles by which cofactors regulate AR transcriptional activity may provide therapeutic advancement for prostate cancer (PCa). The DEAD box RNA helicase p68 (Ddx5) was identified as a novel AR-interacting protein by yeast two-hybrid screening, and we sought to examine the involvement of p68 in AR signaling and PCa. The p68-AR interaction was verified by colocalization of overexpressed protein by immunofluorescence and confirmed in vivo by coimmunoprecipitation in the PCa LNCaP cell line. Chromatin immunoprecipitation in the same cell line showed AR and p68 recruitment to the promoter region of the androgen-responsive prostate-specific antigen (PSA) gene. Luciferase reporter, minigene splicing assays, and RNA interference (RNAi) were used to examine a functional role of p68 in AR-regulated gene expression, whereby p68 targeted RNAi reduced AR-regulated PSA expression, and p68 enhanced AR-regulated repression of CD44 splicing (P = 0.008). Tyrosine phosphorylation of p68 was found to enhance coactivation of ligand-dependent transcription of AR-regulated luciferase reporters independent of ATP-binding. Finally, we observe increased frequency and expression of p68 in PCa compared with benign tissue using a comprehensive prostate tissue microarray (P = 0.003; P = 0.008). These findings implicate p68 as a novel AR transcriptional coactivator that is significantly overexpressed in PCa with a possible role in progression to hormone-refractory disease.

      • Date: 01-10-2008
      • Journal: Cancer Research
      • Volume: 68
      • Issue: 19
      • Pages: 7938-7946
      • Publisher: American Association for Cancer Research
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: p68 DEAD Box RNA helicase • Androgen Receptor • Prostate Cancer • Tyrosine Kinase c-Abl • Alternative Splicing

      Staff

      Dr Emma Clark
      Research Associate

      Dr Luke Gaughan
      Lecturer

      Dr Rakesh Heer
      Joint CRUK/RCS(Eng) Clinician Scientist Fellow and hon. Consultant Urological Surgeon

      Professor Craig Robson
      Professor of Molecular Urology