Epigenetic silencing of EYA2 in pancreatic adenocarcinomas promotes tumor growth.
Oncotarget
; 5(9): 2575-87, 2014 May 15.
Article
em En
| MEDLINE
| ID: mdl-24810906
ABSTRACT
To identify potentially important genes dysregulated in pancreatic cancer, we analyzed genome-wide transcriptional analysis of pancreatic cancers and normal pancreatic duct samples and identified the transcriptional coactivator, EYA2 (Drosophila Eyes Absent Homologue-2) as silenced in the majority of pancreatic cancers. We investigated the role of epigenetic mechanisms of EYA2 gene silencing in pancreatic cancers, performed in vitro and in vivo proliferation and migration assays to assess the effect of EYA2 silencing on tumor cell growth and metastasis formation, and expression analysis to identify genes transcriptionally regulated by EYA2. We found loss of tumoral Eya2 expression in 63% of pancreatic cancers (120/189 cases). Silencing of EYA2 expression in pancreatic cancer cell lines correlated with promoter methylation and histone deacetylation and was reversible with DNA methyltransferase and HDAC inhibitors. EYA2 knockdown in pancreatic cancer cell lines increased cell proliferation. Compared to parental pancreatic cancer cells, pancreatic cancers stably-expressing EYA2 grew more slowly and had fewer metastases in orthotopic models. The transcriptional changes after stable expression of EYA2 in pancreatic cancer cells included induction of genes in the TGFbeta pathway. Epigenetic silencing of EYA2 is a common event in pancreatic cancers and stable expression EYA2 limits the growth and metastases of pancreatic adenocarcinoma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pancreáticas
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Proteínas Nucleares
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Adenocarcinoma
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Regulação Neoplásica da Expressão Gênica
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Proteínas Tirosina Fosfatases
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Inativação Gênica
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Epigênese Genética
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Peptídeos e Proteínas de Sinalização Intracelular
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Proliferação de Células
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Estados Unidos