Frequent epigenetic inactivation of XAF1 (XIAP-associated factor 1), a candidate tumor suppressor, by aberrant promoter hypermethylation in human cervical carcinomas / 대한산부인과학회지

ABSTRACT

OBJECTIVE: X-linked inhibitor of apoptosis (XIAP) is the most potent member of IAP family that exerts antiapoptotic effects by interfering with activities of caspases. 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 explore the candidacy of XAF1, Smac/DIABLO and HtrA2 as a tumor suppressor in cervical carcinogenesis and determine the mechanisms of altered XAF1 expression. METHODS: We investigated the expression and mutation status of the genes in 64 cervical cancer tissues, 5 cervical cancer cell lines and 10 normal cervical tissues. RESULTS: XAF1 transcript was not expressed or extremely low levels in 40% (2/5) of cancer cell line and in 31% (20/64) of primary carcinomas whereas Smac/DIABLO and HtrA2 are normally expressed in all cells. As somatic mutations of the gene was not detected, expression of XAF1 transcript was reactivated in all nonexpressor cell lines after 5-aza-2-deoxycytidine treatment. Bisulfite DNA analysis for CpG sites in the promoter region revealed a strong association between CpG sites hypermethylation and gene silencing. CONCLUSION: XAF1 undergoes epigenetic silencing in a considerable proportion of cervical carcinomas by aberrant promoter hypermethylation rather than genetic alterations, and closely associated with reduced gene expression. Although additional studies are required to determine the biological significance of XAF1 inactivation, it will be valuable to examine the expression status of XAF1 could be a clinically useful marker for cancer treatment.