MP49-04 ROLE OF NUCLEAR AND CYTOPLASMIC TBLR1 IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-04 ROLE OF NUCLEAR AND CYTOPLASMIC TBLR1 IN PROSTATE CANCER Garrett Daniels, Yirong Li, Lan Lin Gellert, Jonathan Melamed, Xinyu Wu, David Zhang, Daniel Meruelo, Susan Logan, Ross Basch, and Peng Lee Garrett DanielsGarrett Daniels More articles by this author , Yirong LiYirong Li More articles by this author , Lan Lin GellertLan Lin Gellert More articles by this author , Jonathan MelamedJonathan Melamed More articles by this author , Xinyu WuXinyu Wu More articles by this author , David ZhangDavid Zhang More articles by this author , Daniel MerueloDaniel Meruelo More articles by this author , Susan LoganSusan Logan More articles by this author , Ross BaschRoss Basch More articles by this author , and Peng LeePeng Lee More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1105AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives TBLR1, a core component of the nuclear receptor corepressor (NCoR) complex, shows both co-repressor and co-activator activities on nuclear receptors, although little is known about its effects on Androgen Receptor (AR). AR coactivators have primarily been viewed as pro-proliferative, however increasing evidence shows the importance of AR coactivators in regulating growth suppressive AR target genes. Cofactors may also have different functions depending on their cellular localization, switching from tumor suppressors to oncogenes or vice versa. In our study, we aim to assess the cofactor TBLR1 function, expression, and localization in prostate cancer. Methods Dual luciferase assays were performed using a reporter plasmid containing 4X androgen response elements. pBabe vector containing TBLR1 fusion proteins with the strong NLS(PKKKRKV) or NES (MLQKKLEELE) fused to the N-terminus was used to create stable cell lines and proliferation was measured by WST-1 assay. RNA levels were measured using quantitative RT-PCR and protein levels were measured by western blotting. ChIP was performed to determine the activation of AR target genes by TBLR1. Immunohistochemistry using TBLR1 antibody was performed on prostate cancer tissue microarray. Results We showed TBLR1 functions as a coactivator of AR in prostate cancer cells and the activation is both phosphorylation and 19S proteosome dependent. TBLR1 primarily localizes in the nucleus in benign prostate cell lines and tissue. In contrast, there is a significant reduction in nuclear TBLR1 expression in prostate cancer (PCa) cell lines and human tissue. Serum starvation induced growth arrest in cancer cells leads to translocation of TBLR1 expression from cytoplasmic to nuclear. Stable ectopic expression of nuclear TBLR1 leads to in vitro and in vivo growth suppression in AR-positive LNCaP cells by activation of androgen regulated genes responsible for differentiation/growth suppression of the prostate (e.g. NKX3.1, KRT18). Interestingly however, TBLR1 expressed in the cytoplasm promotes growth and growth in androgen free conditions. Conclusions There are distinct tumor suppressor and oncogenic functions of nuclear TBLR1 and cytoplasmic TBLR1 respectively. Nuclear TBLR1 selectively activates AR target genes important for growth suppression, whereas cytoplasmic TBLR1 plays a role in promoting growth in the absence of androgens. Further characterizing the role of TBLR1 in prostate could provide novel insights in developing strategies for prostate cancer therapy. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e503 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Garrett Daniels More articles by this author Yirong Li More articles by this author Lan Lin Gellert More articles by this author Jonathan Melamed More articles by this author Xinyu Wu More articles by this author David Zhang More articles by this author Daniel Meruelo More articles by this author Susan Logan More articles by this author Ross Basch More articles by this author Peng Lee More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...