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

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

Author information

1
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030;
2
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
3
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131; Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
4
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil;
5
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
6
Candiolo Cancer Institute and Department of Oncology, University of Turin, Candiolo 10060, Italy;
7
University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Division of Hematology/Oncology, University of New Mexico School of Medicine, Albuquerque, NM 87131;
8
Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
9
International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil;
10
Human Genetics Foundation, Torino 10126, Italy;
11
Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030;
12
Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
13
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
14
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Center for RNA Interference and Noncoding RNA, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
15
Ludwig Institute for Cancer Research, University of California-San Diego, La Jolla, CA 92093; wcavenee@ucsd.edu emmanuel@cipe.accamargo.org.br rpasqual@salud.unm.edu warap@salud.unm.edu.
16
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil; Institute of Psychiatry, University of São Paulo Medical School, São Paulo 01060, Brazil wcavenee@ucsd.edu emmanuel@cipe.accamargo.org.br rpasqual@salud.unm.edu warap@salud.unm.edu.
17
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131; Division of Molecular Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; wcavenee@ucsd.edu emmanuel@cipe.accamargo.org.br rpasqual@salud.unm.edu warap@salud.unm.edu.
18
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; University of New Mexico Cancer Center, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030; Division of Hematology/Oncology, University of New Mexico School of Medicine, Albuquerque, NM 87131; wcavenee@ucsd.edu emmanuel@cipe.accamargo.org.br rpasqual@salud.unm.edu warap@salud.unm.edu.

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.

KEYWORDS:

ADAR; PCA3; PRUNE2; long noncoding RNA; prostate cancer

PMID:
26080435
PMCID:
PMC4500257
DOI:
10.1073/pnas.1507882112
[Indexed for MEDLINE]
Free PMC Article

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