Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines.
Clin Cancer Res
; 10(23): 8094-104, 2004 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-15585645
ABSTRACT
PURPOSE:
Estrogen receptor alpha (ERalpha)-positive breast cancer cell lines are up to 10 times more sensitive than ERalpha-negative cell lines to the antiproliferative activity of the histone deacetylase inhibitor trichostatin A (TSA). The purpose of the study was to investigate the mechanisms underlying this differential response. EXPERIMENTAL DESIGN ANDRESULTS:
In the ERalpha-positive MCF-7 cell line, TSA repressed ERalpha and cyclin D1 transcription and induced ubiquitin dependent proteasomal degradation of cyclin D1, leading primarily to G(1)-S-phase cell cycle arrest. By contrast, cyclin D1 degradation was enhanced but its transcription unaffected by TSA in the ERalpha-negative MDA-MB-231 cell line, which arrested in G(2)-M phase. Cyclin D1 degradation involved Skp2/p45, a regulatory component of the Skp1/Cullin/F-box complex; silencing SKP2 gene expression by RNA interference stabilized cyclin D1 and abrogated the cyclin D1 down-regulation response to TSA.CONCLUSIONS:
Tamoxifen has been shown to inhibit ERalpha-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ERalpha-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regulation through both ERalpha-dependent and ERalpha-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.
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Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
/
Neoplasias Uterinas
/
Neoplasias da Mama
/
Ciclina D1
/
Receptor alfa de Estrogênio
/
Ácidos Hidroxâmicos
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article