Frequent Epigenetic Inactivation of XAF1 by Promotor Hypermethylation in Human Colon Cancers.
- Author:
Jae Young JANG
1
;
Hyo Jong KIM
;
Sung Gil CHI
;
Kil Yeon LEE
;
Ki Deuk NAM
;
Nam Hoon KIM
;
Sang Kil LEE
;
Kwang Ro JOO
;
Seok Ho DONG
;
Byung Ho KIM
;
Young Woon CHANG
;
Joung Il LEE
;
Rin CHANG
Author Information
1. Departments of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea. hjkim@khmc.or.kr
- Publication Type:Original Article ; English Abstract
- Keywords:
XAF1;
Gene, Tumor suppressor;
Colonic neoplasms;
Apoptosis
- MeSH:
Cell Line, Tumor;
Colonic Neoplasms/*genetics;
*DNA Methylation;
English Abstract;
Gene Expression Regulation, Neoplastic;
*Gene Silencing;
Humans;
Intracellular Signaling Peptides and Proteins/genetics;
Mitochondrial Proteins/genetics;
Neoplasm Proteins/*genetics;
Promoter Regions (Genetics);
Serine Endopeptidases/genetics
- From:The Korean Journal of Gastroenterology
2005;45(4):285-293
- CountryRepublic of Korea
- Language:Korean
-
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.
