Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential

Journal of Cellular and Molecular Medicine

Mafalda Almeida³  Vera L. Costa³  Natália R. Costa³  João Ramalho-Carvalho³  Tiago Baptista³  Franclim R. Ribeiro⁴  Paula Paulo⁴  Manuel R. Teixeira⁴  Jorge Oliveira¹  Ragnhild A. Lothe²  Guro E. Lind²  Rui Henrique³ 

[1] Department of Urology, Portuguese Oncology Institute - Porto, Porto, Portugal;Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway;Cancer Biology and Epigenetics Group, Research Center of the Portuguese Oncology Institute - Porto, Porto, Portugal;Cancer Genetics Group, Research Center of the Portuguese Oncology Institute - Porto, Porto, Portugal

关键词: DNA methylation;    prostate cancer;    EFEMP1;    diagnosis;    biomarker;    histone post‐translational modifications;   

DOI  :  10.1111/jcmm.12394

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

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