Frequent Epigenetic Inactivation of XAF1 by Promotor Hypermethylation in Human Colon Cancers / 대한소화기학회지
The Korean Journal of Gastroenterology
;
: 285-293, 2005.
Artigo
em Coreano
| WPRIM
| ID: wpr-16719
ABSTRACT
BACKGROUND/AIMS:
X-linked inhibitor of apoptosis (XIAP) is the most potent member of the IAP family that exerts antiapoptotic effects. Recently, XIAP-associated factor 1 (XAF1) and two mitochondrial proteins, Smac/DIABLO and HtrA2, have been identified to negatively regulate the caspase-inhibiting activity of XIAP. We explored the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in colonic carcinogenesis.METHODS:
Expression and mutation status of the genes in 10 colorectal carcinoma cell lines and 40 primary tumors were examined by quantitative PCR analysis.RESULTS:
XAF1 transcript was not expressed or present at extremely low levels in 60% (6/10) of cancer cell lines whereas Smac/DIABLO and HtrA2 are normally expressed in all cell lines examined. Tumor-specific loss or reduction of XAF1 was also found in 35% (14/40) of matched tissue sets obtained from the same patients. XAF1 transcript was reactivated in all the low expressor cell lines by treatment with the demethylating agent 5-aza-2'-deoxycytidine. Moreover, bisulfite DNA sequencing analysis for 34 CpG sites in the promoter region revealed a strong association between hypermethylation and gene silencing. Restoration of XAF1 expression resulted in enhanced apoptotic response to etoposide and 5-flurouracil, whereas knockdown of XAF1 expression by siRNA transfection significantly inhibited chemotherapeutic drug-induced apoptosis.CONCLUSIONS:
XAF1 undergoes epigenetic gene silencing in a considerable proportion of human colon cancers by aberrant promoter hypermethylation, suggesting that XAF1 inactivation might be implicated in colonic tumorigenesis.
Texto completo:
DisponíveL
Índice:
WPRIM (Pacífico Ocidental)
Assunto principal:
Resumo em Inglês
/
Serina Endopeptidases
/
Regulação Neoplásica da Expressão Gênica
/
Regiões Promotoras Genéticas
/
Neoplasias do Colo
/
Metilação de DNA
/
Inativação Gênica
/
Proteínas Mitocondriais
/
Linhagem Celular Tumoral
/
Peptídeos e Proteínas de Sinalização Intracelular
Tipo de estudo:
Estudo prognóstico
Limite:
Humanos
Idioma:
Coreano
Revista:
The Korean Journal of Gastroenterology
Ano de publicação:
2005
Tipo de documento:
Artigo
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