title: Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer.
abstract: Overwhelming evidence indicates that cancer is a genetic disease caused by the accumulation of mutations in oncogenes and tumor suppressor genes. It is also increasingly apparent, however, that cancer depends not only on mutations in these coding genes but also on alterations in the large class of non-coding RNAs. Here, we report that one such long non-coding RNA, TRPM2-AS, an antisense transcript of TRPM2, which encodes an oxidative stress-activated ion channel, is overexpressed in prostate cancer (PCa). The high expression of TRPM2-AS and its related gene signature were found to be linked to poor clinical outcome, with the related gene signature working also independently of the patient's Gleason score. Mechanistically, TRPM2-AS knockdown led to PCa cell apoptosis, with a transcriptional profile that indicated an unbearable increase in cellular stress in the dying cells, which was coupled to cell cycle arrest, an increase in intracellular hydrogen peroxide and activation of the sense TRPM2 gene. Moreover, targets of existing drugs and treatments were found to be consistently associated with high TRPM2-AS levels in both targeted cells and patients, ultimately suggesting that the measurement of the expression levels of TRPM2-AS allows not only for the early identification of aggressive PCa tumors, but also identifies a subset of at-risk patients who would benefit from currently available, but mostly differently purposed, therapeutic agents.
authors.affiliation: San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Milan, Italy.
authors.forename: U
authors.initials: U
authors.lastname: Orfanelli
authors.affiliation: San Raffaele Scientific Institute, Cellular Immunology Unit, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Jachetti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Chiacchiera
authors.affiliation: San Raffaele Scientific Institute, Cellular Immunology Unit, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Grioni
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology (INSPE), Laboratory of Genetics of Neurological Complex Disorders, Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Brambilla
authors.affiliation: San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Department of Urology, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Briganti
authors.affiliation: Department of Pathology, Vita-Salute University San Raffaele, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Freschi
authors.affiliation: San Raffaele Scientific Institute, Division of Neuroscience, Institute of Experimental Neurology (INSPE), Laboratory of Genetics of Neurological Complex Disorders, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Martinelli-Boneschi
authors.affiliation: Department of Pathology, Vita-Salute University San Raffaele, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Doglioni
authors.affiliation: San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Department of Urology, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Montorsi
authors.affiliation: San Raffaele Scientific Institute, Cellular Immunology Unit, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Bellone
authors.affiliation: San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Casari
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Pasini
authors.affiliation: San Raffaele Scientific Institute, Vita-Salute San Raffaele University and Center for Translational Genomics and Bioinformatics, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Lavorgna
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D018384:Oxidative Stress / Q000235:genetics; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D034622:RNA Interference; D016372:RNA, Antisense / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; D016372:RNA, Antisense; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D006861:Hydrogen Peroxide