Allelic imbalance (AI) on chromosome arm 22q has been detected in 20%-40% of colorectal cancers, suggesting that this chromosome arm has a tumor-suppressor gene involved in colorectal carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, that is deleted, mutated, and hypermethylated in more than 50% of lung cancers. In the present study, we analyzed genetic and epigenetic alterations of the MYO18B gene in colorectal cancers. AI at the MYO18B locus was detected in 16 of 43 (40%) informative cases. Mutations of the MYO18B gene were detected in 2 of 11 (18%) cell lines and 1 of 47 (2%) surgical specimens. Nine of 11 (82%) cell lines showed reduced MYO18B expression, which was restored in all 9 by treatment with 5-aza-2'-deoxycytidine and/or trichostatin A (TSA). Although hypermethylation of the promoter CpG island for MYO18B was not detected, a significant correlation was observed between the level of MYO18B expression and the level of acetylation of histones H3 and H4 in 6 cell lines with and without TSA treatment. Thus, it was suggested that MYO18B is inactivated in a considerable fraction of colorectal cancers by several mechanisms, especially silencing by histone deacetylation and/or AI. Furthermore, restoration of MYO18B expression in colorectal cancer cell lines HT29 and DLD-1 suppressed anchorage-independent growth, whereas it did not affect the growth rate in vitro. These results suggest that genetic and epigenetic inactivation of the MYO18B gene play an important role in colorectal carcinogenesis.
Copyright 2005 Wiley-Liss, Inc.