Oncogenic roles of SETDB2 histone methyltransferase in gastric cancer

Histone H3 lysine 9 tri-methyltransferases (H3K9me3) are related to transcriptional gene silencing. Although SETDB2 has H3K9me3 activity, it is unknown whether SETDB2 is linking to carcinogenesis. Here, we studied alterations and functions of SETDB2 in gastric cancers (GCs). In human clinical samples, overexpression of SETDB2 protein was observed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts, and significantly associated with poor prognosis of the patients (P<0.05). SETDB2 protein was significantly detected in late stage of GCs. Moreover, SETDB2 protein was strongly expressed in four (30.8%) of 13 GC cell lines, and knockdown of SETDB2 led to decrease the cell proliferation, migration and invasion. According to the microarray analysis on a GC cell line after knockdown of SETDB2, the expression of WWOX and CADM1 tumor suppressor genes was significantly up-regulated. ChIP analysis showed that the H3K9me3 levels at the promoter regions of WWOX and CADM1 genes were closely regulated by the SETDB2 in GC cells. We also found that SETDB2 bound to the promoter regions after SETDB2 overexpression. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, through H3K9me3, and hence overexpression of SETDB2 may contribute to gastric progression. Transfection of SETDB2 siRNA into MKN74 cells were performed by electroporation. After 48hrs, cells were harvested. Total RNA was used for cDNA microarray.