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Chromosomal loss of 18q21 is a frequent event in colorectal cancer (CRC) development, suggesting that this region harbors tumor suppressor genes (TSGs). Several candidate TSGs, among which methyl-CpG-binding domain protein 1 (MBD1), CpG-binding proteinCXXC1, Sma- and Mad-related protein 4 (SMAD4), deleted in colon cancer (DCC) and methyl-CpG-binding domain protein 2 (MBD2) are closely linked on a 4-Mb DNA region on chromosome18q21. As TSGs can be epigenetically silenced, this study investigates whetherMBD1,CXXC1,SMAD4,DCCandMBD2are subject to epigenetic silencing in CRC. Methylation-specific polymerase chain reaction and sodium bisulfite sequencing of these genes show thatDCC, but notMBD1,CXXC1,SMAD4andMBD2, has promoter CpG island methylation in CRC cell lines and tissues {normal mucosa [29.5% (18/61)], adenomas [81.0% (47/58)] and carcinomas [82.7% (62/75)] (P = 8.6 × 10−9)} that is associated with reducedDCCexpression, independent of 18q21 loss analyzed by multiplex ligation-dependent probe amplification. Reduced gene expression ofCXXC1,SMAD4andMBD2correlates with 18q21 loss in CRC cell lines (P = 0.04, 0.02 and 0.02, respectively). Treatment with the demethylating agent 5-aza-2′-deoxycytidine, but not with the histone deacetylase inhibitor trichostatin A exclusively restoredDCCexpression in CRC cell lines. Chromatin immunoprecipitation studies reveal that theDCCpromoter is marked with repressive histone-tail marks H3K9me3 and H3K27me3, whereas activity related H3K4me3 was absent. Only active epigenetic marks were detected forMBD1,CXXC1,SMAD4andMBD2. This study demonstrates specific epigenetic silencing ofDCCin CRC as a focal process not affecting neighboring genes on chromosomal region 18q21.

carcinogenesis

Promoter CpG island hypermethylation- and H3K9me3 and H3K27me3-mediated epigenetic silencing targets the deleted in colon cancer (DCC) gene in colorectal carcinogenesis without affecting neighboring genes on chromosomal region 18q21