619 EPIGENETIC CONTROL OF ANDROGEN ENRICHED LAMIN DEFINED MICRODOMAINS (LDMDS) IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011619 EPIGENETIC CONTROL OF ANDROGEN ENRICHED LAMIN DEFINED MICRODOMAINS (LDMDS) IN PROSTATE CANCER Brian T. Helfand, Yuanyuan Wang, Pekka Taiman, Katrin Pfleghaar, Robert D. Goldman, and Dale K. Shumaker Brian T. HelfandBrian T. Helfand Chicago, IL More articles by this author , Yuanyuan WangYuanyuan Wang Chicago, IL More articles by this author , Pekka TaimanPekka Taiman Chicago, IL More articles by this author , Katrin PfleghaarKatrin Pfleghaar Munich, Germany More articles by this author , Robert D. GoldmanRobert D. Goldman Chicago, IL More articles by this author , and Dale K. ShumakerDale K. Shumaker Chicago, IL More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1472AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Altered nuclear shape and DNA content have reproducibly been described in prostate cancer (CaP) specimens and are predictive of disease progression and metastasis. Nuclear lamin intermediate filaments are key determinants of nuclear size and shape and play a role in both DNA synthesis and transcription. We have shown that lamin-defined microdomains (LDMDs) are induced by knocking down lamin B1 (LB1) using shRNA. These LDMDs are enriched in euchromatin, accumulate activated RNA polymerase II (Pol IIo), are decreased in epigenetic histone marks for RNA elongation, and preferentially localize chromosome regions. The present study, 1) determined whether LDMDs are present within CaP cells and tissue and 2) characterized LDMD content. METHODS CaP tissue microarrays and human CaP cell lines with various invasive potential (DU-145, LNCaP, PC-3) were used. The presence and content of LDMDs were assayed using antibodies directed against lamin A/C, lamin B1, histone marks [AcH3 (euchromatin), H3K27me3 and H3K9me3 (heterochromatin), H3K36me3 (elongation phase of transcription)], Pol IIo and androgen receptor (AR). Transcription was assayed with BrUTP incorporation. RESULTS In CaP cells, LDMD presence appears to be correlated with disease aggressiveness and invasive potential. There was an increased frequency of LDMDs in high Gleason ≥8 disease vs. low grade (Gleason ≤6) disease (10.2% v. 2.1%; p<0.001). Based on immunostaining of epigenetic histone marks (AcH3, H3K27me3 and H3K9me3), LDMDs contain euchromatin which suggests a transcriptionally active microdomain. This is supported by the finding that LDMDs accumulate Pol IIo, and AR. Surprisingly, LDMDs are devoid of histone marks for the elongation phase of transcription and do not incorporate BrUTP. CONCLUSIONS LDMDs are present in CaP cells and their frequency appears to be correlated with tumor aggressiveness. LDMDs appear to be enriched for euchromatin. Although LDMDs accumulate AR and Pol IIo they appear to define a promoter proximal stalled state for Pol II. These studies will provide significant insights into the functions of LDMDs and will help to elucidate the mechanisms underlying the development and progression of aggressive CaP. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e249 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Brian T. Helfand Chicago, IL More articles by this author Yuanyuan Wang Chicago, IL More articles by this author Pekka Taiman Chicago, IL More articles by this author Katrin Pfleghaar Munich, Germany More articles by this author Robert D. Goldman Chicago, IL More articles by this author Dale K. Shumaker Chicago, IL More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...