title: Deregulation of an imprinted gene network in prostate cancer.
abstract: Multiple epigenetic alterations contribute to prostate cancer progression by deregulating gene expression. Epigenetic mechanisms, especially differential DNA methylation at imprinting control regions (termed DMRs), normally ensure the exclusive expression of imprinted genes from one specific parental allele. We therefore wondered to which extent imprinted genes become deregulated in prostate cancer and, if so, whether deregulation is due to altered DNA methylation at DMRs. Therefore, we selected presumptive deregulated imprinted genes from a previously conducted in silico analysis and from the literature and analyzed their expression in prostate cancer tissues by qRT-PCR. We found significantly diminished expression of PLAGL1/ZAC1, MEG3, NDN, CDKN1C, IGF2, and H19, while LIT1 was significantly overexpressed. The PPP1R9A gene, which is imprinted in selected tissues only, was strongly overexpressed, but was expressed biallelically in benign and cancerous prostatic tissues. Expression of many of these genes was strongly correlated, suggesting co-regulation, as in an imprinted gene network (IGN) reported in mice. Deregulation of the network genes also correlated with EZH2 and HOXC6 overexpression. Pyrosequencing analysis of all relevant DMRs revealed generally stable DNA methylation between benign and cancerous prostatic tissues, but frequent hypo- and hyper-methylation was observed at the H19 DMR in both benign and cancerous tissues. Re-expression of the ZAC1 transcription factor induced H19, CDKN1C and IGF2, supporting its function as a nodal regulator of the IGN. Our results indicate that a group of imprinted genes are coordinately deregulated in prostate cancers, independently of DNA methylation changes.
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany.
authors: Teodora
authors: T
authors: Ribarska
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany.
authors: Wolfgang
authors: W
authors: Goering
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany.
authors: Johanna
authors: J
authors: Droop
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany.
authors: Klaus-Marius
authors: KM
authors: Bastian
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany; Institute for Anatomy II; Heinrich Heine University; Düsseldorf, Germany.
authors: Marc
authors: M
authors: Ingenwerth
authors: Department of Urology; Heinrich Heine University; Düsseldorf, Germany.
authors: Wolfgang A
authors: WA
authors: Schulz
mesh_terms: D000728:Androgens / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099273:Neurabins
chemical_list: D000728:Androgens; D018797:Cell Cycle Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D018398:Homeodomain Proteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D063151:Polycomb Repressive Complex 2; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D025521:Tumor Suppressor Proteins; D000099273:Neurabins; C072312:ERG protein, human; C094289:HOXC6 protein, human; C106464:PLAGL1 protein, human; C498409:EZH2 protein, human
keywords: DNA methylation; ZAC1; cancer epigenetics; differentially methylated region; imprinted gene network; imprinted genes; prostate cancer; pyrosequencing