Salameh Ahmad, Lee Alessandro K, Cardó-Vila Marina, Nunes Diana N, Efstathiou Eleni, Staquicini Fernanda I, Dobroff Andrey S, Marchiò Serena, Navone Nora M, Hosoya Hitomi, Lauer Richard C, Wen Sijin, Salmeron Carolina C, Hoang Anh, Newsham Irene, Lima Leandro A, Carraro Dirce M, Oliviero Salvatore, Kolonin Mikhail G, Sidman Richard L, Do Kim-Anh, Troncoso Patricia, Logothetis Christopher J, Brentani Ricardo R, Calin George A, Cavenee Webster K, Dias-Neto Emmanuel, Pasqualini Renata, Arap Wadih
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;
David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
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.
前列腺癌抗原3（PCA3）是最具特异性的前列腺癌生物标志物，但其功能仍不清楚。在此，我们鉴定出PRUNE2，一个携带PCA3基因座的靶蛋白编码基因变体，从而将PCA3归类为反义内含子长链非编码（lnc）RNA。我们表明，PCA3通过一种独特的调控机制控制PRUNE2水平，该机制涉及形成PRUNE2/PCA3双链RNA，其经历作用于RNA的腺苷脱氨酶（ADAR）依赖性腺苷到肌苷的RNA编辑。前列腺癌细胞中PRUNE2的表达或沉默分别降低和增加细胞增殖。此外，PRUNE2和PCA3对免疫缺陷荷瘤小鼠的肿瘤生长产生相反的影响。在人前列腺癌标本中证实了PRUNE2和PCA3的共同调控和RNA编辑，支持了我们研究结果的医学相关性。这些结果确立了PCA3作为人前列腺癌中的显性负癌基因和PRUNE2作为未被认识的肿瘤抑制基因，并且它们的调控轴代表了诊断和治疗干预的独特分子靶点。
