Epigenetic regulation of gelsolin expression in human breast cancer cells.
Exp Cell Res
; 249(1): 161-76, 1999 May 25.
Article
em En
| MEDLINE
| ID: mdl-10328963
ABSTRACT
Gelsolin is a multifunctional, actin-binding protein that is greatly decreased in many transformed cell lines and tumor tissues, including breast cancers. Downregulation of gelsolin RNA occurs in most breast cancers of rats, mice, and humans, but gross mutations of the gelsolin gene have not been found. Here we demonstrate by PCR and RT-PCR analysis that there are no point mutations in putative regulatory regions or the entire coding region of the cytoplasmic isoform of the gelsolin gene in human breast cancer cells (BCC). To determine if epigenetic modification is involved in downregulating gelsolin expression in MDA-MB-231 (MDA231), MCF7, and T47D BCC, we have used Southern blot analysis, 5-azacytidine (5aza) treatment, and trichostatin A (TSA) treatment. Southern blot analysis performed on genomic DNA demonstrated altered CpG methylation within intron 1 in DNA from all BCC compared to normal, mortal human mammary epithelial cells (HMEC). Treatment of the BCC with 5aza converted the DNA restriction pattern to that seen in untreated HMEC genomic DNA and caused modest increases in gelsolin RNA and protein. Incubation with TSA, an inhibitor of histone deacetylase, induced a dramatic upregulation of gelsolin RNA and protein levels which preceded apoptotic death of all BCC within 48-60 h. Our data support a role for epigenetic changes in chromatin structure leading to downregulation of gelsolin expression in human breast cancer. To our knowledge, this is the first example of a tumor suppressor gene downregulated in human breast cancer by changes in histone acetylation.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Histonas
/
Regulação Neoplásica da Expressão Gênica
/
Processamento de Proteína Pós-Traducional
/
Gelsolina
/
Proteínas de Neoplasias
Limite:
Female
/
Humans
Idioma:
En
Revista:
Exp Cell Res
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Estados Unidos