Frequent Epigenetic Inactivation of XAF1 by Promotor Hypermethylation in Human Colon Cancers / 대한소화기학회지
The Korean Journal of Gastroenterology
;
: 285-293, 2005.
Article
in Korean
| 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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
English Abstract
/
Serine Endopeptidases
/
Gene Expression Regulation, Neoplastic
/
Promoter Regions, Genetic
/
Colonic Neoplasms
/
DNA Methylation
/
Gene Silencing
/
Mitochondrial Proteins
/
Cell Line, Tumor
/
Intracellular Signaling Peptides and Proteins
Type of study:
Prognostic study
Limits:
Humans
Language:
Korean
Journal:
The Korean Journal of Gastroenterology
Year:
2005
Type:
Article
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