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

Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):8403-8. doi: 10.1073/pnas.1507882112. Epub 2015 Jun 15.


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.

Keywords: ADAR; PCA3; PRUNE2; long noncoding RNA; prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism
  • Animals
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Introns / genetics*
  • MCF-7 Cells
  • Male
  • Mice, SCID
  • Molecular Sequence Data
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • RNA Interference
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • RNA, Long Noncoding / genetics*
  • RNA, Long Noncoding / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays / methods


  • Antigens, Neoplasm
  • Neoplasm Proteins
  • PRUNE2 protein, human
  • RNA Precursors
  • RNA, Long Noncoding
  • Tumor Suppressor Proteins
  • prostate cancer antigen 3, human
  • ADAR1 protein, mouse
  • Adenosine Deaminase

Associated data

  • GENBANK/FJ808772
  • GENBANK/FJ808773