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Epigenetic dysregulation of key developmental genes in radiation-induced rat mammary carcinomas.
Daino, Kazuhiro; Nishimura, Mayumi; Imaoka, Tatsuhiko; Takabatake, Masaru; Morioka, Takamitsu; Nishimura, Yukiko; Shimada, Yoshiya; Kakinuma, Shizuko.
Afiliação
  • Daino K; Department of Radiation Effects Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
  • Nishimura M; Department of Radiation Effects Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
  • Imaoka T; Department of Radiation Effects Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
  • Takabatake M; QST Advanced Study Laboratory, QST, Chiba, Japan.
  • Morioka T; Department of Radiological Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan.
  • Nishimura Y; Department of Radiation Effects Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
  • Shimada Y; Department of Radiological Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, Japan.
  • Kakinuma S; Department of Radiation Effects Research, National Institute of Radiological Sciences (NIRS), National Institutes for Quantum and Radiological Science and Technology (QST), Chiba, Japan.
Int J Cancer ; 143(2): 343-354, 2018 07 15.
Article em En | MEDLINE | ID: mdl-29435983
ABSTRACT
With the increase in the number of long-term cancer survivors worldwide, there is a growing concern about the risk of secondary cancers induced by radiotherapy. Epigenetic modifications of genes associated with carcinogenesis are attractive targets for the prevention of cancer owing to their reversible nature. To identify genes with possible changes in functionally relevant DNA methylation patterns in mammary carcinomas induced by radiation exposure, we performed microarray-based global DNA methylation and expression profiling in γ-ray-induced rat mammary carcinomas and normal mammary glands. The gene expression profiling identified dysregulation of developmentally related genes, including the downstream targets of polycomb repressive complex 2 (PRC2) and overexpression of enhancer of zeste homolog 2, a component of PRC2, in the carcinomas. By integrating expression and DNA methylation profiles, we identified ten hypermethylated and three hypomethylated genes that possibly act as tumor-suppressor genes and oncogenes dysregulated by aberrant DNA methylation; half of these genes encode developmental transcription factors. Bisulfite sequencing and quantitative PCR confirmed the dysregulation of the polycomb-regulated developmentally related transcription-factor genes Dmrt2, Hoxa7, Foxb1, Sox17, Lhx8, Gata3 and Runx1. Silencing of Hoxa7 was further verified by immunohistochemistry. These results suggest that, in radiation-induced mammary gland carcinomas, PRC2-mediated aberrant DNA methylation leads to dysregulation of developmentally related transcription-factor genes. Our findings provide clues to molecular mechanisms linking epigenetic regulation and radiation-induced breast carcinogenesis and underscore the potential of such epigenetic mechanisms as targets for cancer prevention.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Análise de Sequência de DNA / Metilação de DNA / Perfilação da Expressão Gênica / Neoplasias Mamárias Experimentais / Neoplasias Induzidas por Radiação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Análise de Sequência de DNA / Metilação de DNA / Perfilação da Expressão Gênica / Neoplasias Mamárias Experimentais / Neoplasias Induzidas por Radiação Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article