title: Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer.
abstract: BACKGROUND
  Ultraconserved regions (UCR) are genomic segments of more than 200 base pairs that are evolutionarily conserved among mammalian species. They are thought to have functions as transcriptional enhancers and regulators of alternative splicing. Recently, it was shown that numerous RNAs are transcribed from these regions. These UCR-encoded transcripts (ucRNAs) were found to be expressed in a tissue- and disease-specific manner and may interfere with the function of other RNAs through RNA: RNA interactions. We hypothesized that ucRNAs have unidentified roles in the pathogenesis of human prostate cancer. In a pilot study, we examined ucRNA expression profiles in human prostate tumors.
  
  
  METHODS
  Using a custom microarray with 962 probesets representing sense and antisense sequences for the 481 human UCRs, we examined ucRNA expression in resected, fresh-frozen human prostate tissues (57 tumors, 7 non-cancerous prostate tissues) and in cultured prostate cancer cells treated with either epigenetic drugs (the hypomethylating agent, 5-Aza 2'deoxycytidine, and the histone deacetylase inhibitor, trichostatin A) or a synthetic androgen, R1881. Expression of selected ucRNAs was also assessed by qRT-PCR and NanoString®-based assays. Because ucRNAs may function as RNAs that target protein-coding genes through direct and inhibitory RNA: RNA interactions, computational analyses were applied to identify candidate ucRNA:mRNA binding pairs.
  
  
  RESULTS
  We observed altered ucRNA expression in prostate cancer (e.g., uc.106+, uc.477+, uc.363 + A, uc.454 + A) and found that these ucRNAs were associated with cancer development, Gleason score, and extraprostatic extension after controlling for false discovery (false discovery rate < 5% for many of the transcripts). We also identified several ucRNAs that were responsive to treatment with either epigenetic drugs or androgen (R1881). For example, experiments with LNCaP human prostate cancer cells showed that uc.287+ is induced by R1881 (P < 0.05) whereas uc.283 + A was up-regulated following treatment with combined 5-Aza 2'deoxycytidine and trichostatin A (P < 0.05). Additional computational analyses predicted RNA loop-loop interactions of 302 different sense and antisense ucRNAs with 1058 different mRNAs, inferring possible functions of ucRNAs via direct interactions with mRNAs.
  
  
  CONCLUSIONS
  This first study of ucRNA expression in human prostate cancer indicates an altered transcript expression in the disease.
authors: Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors: Robert S
authors: RS
authors: Hudson
authors: Ming
authors: M
authors: Yi
authors: Natalia
authors: N
authors: Volfovsky
authors: Robyn L
authors: RL
authors: Prueitt
authors: Dominic
authors: D
authors: Esposito
authors: Stefano
authors: S
authors: Volinia
authors: Chang-Gong
authors: CG
authors: Liu
authors: Aaron J
authors: AJ
authors: Schetter
authors: Katrien
authors: K
authors: Van Roosbroeck
authors: Robert M
authors: RM
authors: Stephens
authors: George A
authors: GA
authors: Calin
authors: Carlo M
authors: CM
authors: Croce
authors: Stefan
authors: S
authors: Ambs
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D000077209:Decitabine; D044127:Epigenesis, Genetic / Q000187:drug effects; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism; D022661:RNA, Untranslated / Q000235:genetics / Q000378:metabolism; D045165:Testosterone Congeners / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D022661:RNA, Untranslated; D045165:Testosterone Congeners; D015741:Metribolone; C012589:trichostatin A; D000077209:Decitabine; D001374:Azacitidine