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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)8403-8408
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number27
DOIs
Publication statusPublished - Jul 7 2015

Keywords

  • ADAR
  • Long noncoding RNA
  • PCA3
  • Prostate cancer
  • PRUNE2

ASJC Scopus subject areas

  • General

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  • Cite this

    Salameh, A., Lee, A. K., Cardó-Vila, M., Nunes, D. N., Efstathiou, E., Staquicini, F. I., Dobroff, A. S., Marchiò, S., Navone, N. M., Hosoya, H., Lauer, R. C., Wen, S., Salmeron, C. C., Hoang, A., Newsham, I., Lima, L. A., Carraro, D. M., Oliviero, S., Kolonin, M. G., ... Arap, W. (2015). PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3. Proceedings of the National Academy of Sciences of the United States of America, 112(27), 8403-8408. https://doi.org/10.1073/pnas.1507882112