title: Epigenetic disruption of miR-130a promotes prostate cancer by targeting SEC23B and DEPDC1.
abstract: MicroRNAs (miRNAs) are small, non-coding RNAs that mediate post-transcriptional gene silencing, fine tuning gene expression. In an initial screen, miRNAs were found to be globally down-regulated in prostate cancer (PCa) cell lines and primary tumours. Exposure of PCa cell lines to a demethylating agent, 5-Aza-CdR resulted in an increase in the expression levels of miRNAs in general. Using stringent filtering criteria miR-130a was identified as the most promising candidate and selected for validation analyses in our patient series. Down-regulation of miR-130a was associated with promoter hypermethylation. MiR-130a methylation levels discriminated PCa from non-malignant tissues (AUC = 0.956), and urine samples revealed high specificity for non-invasive detection of patients with PCa (AUC = 0.89). Additionally, repressive histone marks were also found in the promoter of miR-130a. Over-expression of miR-130a in PCa cells reduced cell viability and invasion capability, and increased apoptosis. Putative targets of miR-130a were assessed by microarray expression profiling and DEPD1C and SEC23B were selected for validation. Silencing of both genes resembled the effect of over-expressing miR-130a in PCa cells. Our data indicate that miR-130a is an epigenetically regulated miRNA involved in regulation of key molecular and phenotypic features of prostate carcinogenesis, acting as a tumour suppressor miRNA.
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Biomedical Sciences Graduate Program, Institute of Biomedical Sciences Abel Salazar - University of Porto (ICBAS-UP), Porto, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: João Barbosa
authors.initials: JB
authors.lastname: Martins
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Lina
authors.initials: L
authors.lastname: Cekaite
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Anita
authors.initials: A
authors.lastname: Sveen
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Torres-Ferreira
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Graça
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Costa-Pinheiro
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway.
authors.forename: Ina Andrassy
authors.initials: IA
authors.lastname: Eilertsen
authors.affiliation: Department of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Antunes
authors.affiliation: Department of Urology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.affiliation: Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), Porto, Portugal. Electronic address: carmenjeronimo@ipoporto.min-saude.pt.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D042002:Chromatin Assembly and Disassembly; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D014162:Transfection; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C584411:DEPDC1 protein, human; D004791:Enzyme Inhibitors; D020690:GTPase-Activating Proteins; D006657:Histones; C554019:MIRN130 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; C543353:SEC23B protein, human; D033921:Vesicular Transport Proteins; D015254:DNA Modification Methylases
keywords: DEPDC1; Prostate cancer; SEC23B; miR's epigenetic regulation; miR-130a; miRNA