title: PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3.
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.
authors.affiliation: 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;
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salameh
authors.affiliation: David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Alessandro K
authors.initials: AK
authors.lastname: Lee
authors.affiliation: 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;
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.affiliation: 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;
authors.forename: Diana N
authors.initials: DN
authors.lastname: Nunes
authors.affiliation: 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;
authors.forename: Eleni
authors.initials: E
authors.lastname: Efstathiou
authors.affiliation: 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;
authors.forename: Fernanda I
authors.initials: FI
authors.lastname: Staquicini
authors.affiliation: 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;
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.affiliation: Candiolo Cancer Institute and Department of Oncology, University of Turin, Candiolo 10060, Italy;
authors.forename: Serena
authors.initials: S
authors.lastname: Marchiò
authors.affiliation: 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;
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.affiliation: David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hosoya
authors.affiliation: 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;
authors.forename: Richard C
authors.initials: RC
authors.lastname: Lauer
authors.affiliation: Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.affiliation: 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;
authors.forename: Carolina C
authors.initials: CC
authors.lastname: Salmeron
authors.affiliation: 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;
authors.forename: Anh
authors.initials: A
authors.lastname: Hoang
authors.affiliation: David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Irene
authors.initials: I
authors.lastname: Newsham
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil;
authors.forename: Leandro A
authors.initials: LA
authors.lastname: Lima
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil;
authors.forename: Dirce M
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Human Genetics Foundation, Torino 10126, Italy;
authors.forename: Salvatore
authors.initials: S
authors.lastname: Oliviero
authors.affiliation: Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030;
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Kolonin
authors.affiliation: Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215;
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.affiliation: 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;
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: 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;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil;
authors.forename: Ricardo R
authors.initials: RR
authors.lastname: Brentani
authors.affiliation: 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;
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.affiliation: 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.
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Dias-Neto
authors.affiliation: 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.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.affiliation: 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.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
mesh_terms: D000243:Adenosine Deaminase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007438:Introns / Q000235:genetics*; D061986:MCF-7 Cells; D008297:Male; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000951:Antigens, Neoplasm; D009363:Neoplasm Proteins; C509845:PRUNE2 protein, human; D012322:RNA Precursors; D062085:RNA, Long Noncoding; D025521:Tumor Suppressor Proteins; C479341:prostate cancer antigen 3, human; C000599465:ADAR1 protein, mouse; D000243:Adenosine Deaminase
keywords: ADAR; PCA3; PRUNE2; long noncoding RNA; prostate cancer