title: Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential.
abstract: Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1's role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall-Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis.
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Porto, Portugal.
authors.forename: Mafalda
authors.initials: M
authors.lastname: Almeida
authors.forename: Vera L
authors.initials: VL
authors.lastname: Costa
authors.forename: Natália R
authors.initials: NR
authors.lastname: Costa
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.forename: Tiago
authors.initials: T
authors.lastname: Baptista
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: Paula
authors.initials: P
authors.lastname: Paulo
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
authors.forename: Jorge
authors.initials: J
authors.lastname: Oliveira
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011499:Protein Processing, Post-Translational
chemical_list: D014408:Biomarkers, Tumor; C119630:EFEMP1 protein, human; D016326:Extracellular Matrix Proteins; D006657:Histones
keywords: DNA methylation; EFEMP1; biomarker; diagnosis; histone post-translational modifications; prostate cancer