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 Sidman; Kim-Anh Do; Patricia Troncoso; Christopher J Logothetis; Ricardo R Brentani; George A Calin; Webster K Cavenee; Emmanuel Dias-Neto; Renata Pasqualini; Wadih Arap

doi:10.1073/pnas.1507882112

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

Journal article

Open access

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, …

Proceedings of the National Academy of Sciences - PNAS, Vol.112(27), pp.8403-8408

07/07/2015

DOI: https://doi.org/10.1073/pnas.1507882112

PMCID: PMC4500257

PMID: 26080435

Abstract

Prostatic Neoplasms - metabolism

Adenosine Deaminase - metabolism

Humans

Gene Expression Regulation, Neoplastic

Molecular Sequence Data

Immunoblotting

Male

Neoplasm Proteins - metabolism

Prostatic Neoplasms - genetics

MCF-7 Cells

RNA Interference

Tumor Suppressor Proteins - genetics

HEK293 Cells

Antigens, Neoplasm - metabolism

RNA Precursors - metabolism

Neoplasm Proteins - genetics

Antigens, Neoplasm - genetics

Prostatic Neoplasms - pathology

Tumor Suppressor Proteins - metabolism

Introns - genetics

Adenosine Deaminase - genetics

RNA Precursors - genetics

RNA, Long Noncoding - genetics

Mice, SCID

Reverse Transcriptase Polymerase Chain Reaction

Xenograft Model Antitumor Assays - methods

Animals

Cell Line, Tumor

Protein Binding

HeLa Cells

RNA, Long Noncoding - metabolism

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.

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Title: PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3
Creators: Ahmad Salameh - 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
Alessandro K Lee - David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
Marina Cardó-Vila - 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
Diana N Nunes - 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
Eleni Efstathiou - 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
Fernanda I Staquicini - 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
Andrey S Dobroff - 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
Serena Marchiò - Candiolo Cancer Institute and Department of Oncology, University of Turin, Candiolo 10060, Italy
Nora M Navone - 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
Hitomi Hosoya - David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
Richard C Lauer - 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
Sijin Wen - Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
Carolina C Salmeron - 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
Anh Hoang - 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
Irene Newsham - David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
Leandro A Lima - International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil
Dirce M Carraro - International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil
Salvatore Oliviero - Human Genetics Foundation, Torino 10126, Italy
Mikhail G Kolonin - Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030
Richard L Sidman - Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215
Kim-Anh Do - Department of Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
Patricia Troncoso - 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
Christopher J Logothetis - 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
Ricardo R Brentani - International Research Center, A.C. Camargo Cancer Center, São Paulo, SP 01508-010 Brazil
George A Calin - 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
Webster K Cavenee - 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
Emmanuel Dias-Neto - 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
Renata Pasqualini - 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
Wadih Arap - 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
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.112(27), pp.8403-8408
Date published: 07/07/2015
Grant note: CA95616 / NCI NIH HHS U54 GM104942 / NIGMS NIH HHS CA90270 / NCI NIH HHS P01 CA095616 / NCI NIH HHS P50 CA090270 / NCI NIH HHS
Academic Unit: Cancer Institute of New Jersey at University Hospital; Radiation Oncology
Language: English
Resource Type: Journal article
Identifiers: 991031654461204646