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      Splicing Factor Prp8 Interacts With NES AR and Regulates Androgen Receptor in Prostate Cancer Cells

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          Abstract

          Androgen receptor (AR) plays a pivotal role in the development of primary as well as advanced castration-resistant prostate cancer. Previous work in our lab identified a novel nuclear export signal (NES) (NES AR) in AR ligand-binding domain essential for AR nucleocytoplasmic trafficking. By characterizing the localization of green fluorescence protein (GFP)-tagged NES AR, we designed and executed a yeast mutagenesis screen and isolated 7 yeast mutants that failed to display the NES AR export function. One of those mutants was identified as the splicing factor pre-mRNA processing factor 8 (Prp8). We further showed that Prp8 could regulate NES AR function using short hairpin RNA knockdown of Prp8 coupled with a rapamycin export assay in mammalian cells and knockdown of Prp8 could induce nuclear accumulation of GFP-tagged AR in PC3 cells. Prp8 expression was decreased in castration-resistant LuCaP35 xenograft tumors as compared with androgen-sensitive xenografts. Laser capture microdissection and quantitative PCR showed Prp8 mRNA levels were decreased in human prostate cancer specimens with high Gleason scores. In prostate cancer cells, coimmunoprecipitation and deletion mutagenesis revealed a physical interaction between Prp8 and AR mainly mediated by NES AR. Luciferase assay with prostate specific antigen promoter-driven reporter demonstrated that Prp8 regulated AR transcription activity in prostate cancer cells. Interestingly, Prp8 knockdown also increased polyubiquitination of endogenous AR. This may be 1 possible mechanism by which it modulates AR activity. These results show that Prp8 is a novel AR cofactor that interacts with NES AR and regulates AR function in prostate cancer cells.

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          Author and article information

          Journal
          Mol Endocrinol
          Mol. Endocrinol
          mend
          molen
          mend
          Molecular Endocrinology
          Endocrine Society (Washington, DC )
          0888-8809
          1944-9917
          December 2015
          15 September 2015
          1 December 2016
          : 29
          : 12
          : 1731-1742
          Affiliations
          Departments of Urology (D.W., M.M.N., K.Z.M., P.S., Y.J., K.O., J.A.D., Z.W.), Pharmacology and Chemical Biology (Z.W.), and Pathology (R.D., Z.W.) and University of Pittsburgh Cancer Institute (R.D., Z.W.), University of Pittsburgh, Pittsburgh, Pennsylvania 15232; and Department of Urology (Y.J.), The First People's Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, China
          Author notes
          Address all correspondence and requests for reprints to: Zhou Wang, PhD, Department of Urology, Shadyside Medical Center, Suite G40, 5200 Centre Avenue, Pittsburgh, PA 15232. E-mail: wangz2@ 123456upmc.edu .
          [*]

          D.W. and M.M.N. contributed equally to this work.

          Article
          PMC4664230 PMC4664230 4664230 ME-15-1112
          10.1210/me.2015-1112
          4664230
          26371515
          bad62389-7103-4d70-a2eb-1c8a81d3c66e
          Copyright © 2015 by the Endocrine Society
          History
          : 21 April 2015
          : 9 September 2015
          Categories
          Original Research

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