Journal Article

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Alessandro K. Lee, Anh Hoang, Mikhail G. Kolonin, Eleni Efstathiou, Emmanuel Dias-Neto, Wadih Arap, Fernanda I. Staquicini, Leandro A. Lima, Webster K. Cavenee, Salameh, Ahmad, Sijin Wen, Andrey S. Dobroff, George A. Calin, Hitomi Hosoya, Dirce M. Carraro, Kim-Anh Do, Christopher J. Logothetis, Richard C. Lauer, Ricardo R. Brentani, Renata Pasqualini, Marina Cardó-Vila, Serena MarchióoÌ, Carolina C. Salmeron, Diana N. Nunes, Salvatore Oliviero, Richard L. Sidman, Nora M. Navone, Irene Newsham, Patricia Troncoso

2015

Overview

Prostate cancer antigen 3 ( PCA3 ) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2 , a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: ADAR / adenosine deaminase / Adenosine Deaminase - genetics / Adenosine Deaminase - metabolism / Animals / Antigens / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / Biological Sciences / Biomarkers / Cell Line, Tumor / cell proliferation / Cells / double-stranded RNA / Gene Expression Regulation, Neoplastic / HEK293 Cells / HeLa Cells / Humans / Immunoblotting / Introns - genetics / loci / long noncoding RNA / Male / MCF-7 Cells / mice / Mice, SCID / Molecular Sequence Data / neoplasm cells / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / non-coding RNA / oncogenes / PCA3 / Prostate cancer / prostatic neoplasms / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Protein Binding / PRUNE2 / Reverse Transcriptase Polymerase Chain Reaction / Ribonucleic acid / RNA / RNA editing / RNA Interference / RNA Precursors - genetics / RNA Precursors - metabolism / RNA, Long Noncoding - genetics / RNA, Long Noncoding - metabolism / Rodents / tumor suppressor genes / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - metabolism / Tumors / Xenograft Model Antitumor Assays - methods