Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer.
Oncogenic roles of the SETDB2 histone methyltransferase in gastric cancer.
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DOI：
10.18632/oncotarget.11625
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发表时间：
2016-10-11
期刊：
影响因子：
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通讯作者：
Tanaka S
中科院分区：
文献类型：
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作者：
Nishikawaji T;Akiyama Y;Shimada S;Kojima K;Kawano T;Eishi Y;Yuasa Y;Tanaka S
SETDB2是一种组蛋白H3赖氨酸9(H3K9)三甲基转移酶，参与转录基因沉默。由于目前尚不清楚SETDB2s是否与癌变有关，我们研究了SETDB2s在人类胃癌(GC)中的变化和功能。免疫组织化学检测72例胃癌组织中有30例(41.7%)呈高表达。SETDB2过度表达与胃癌的晚期(P<；0.05)和预后不良(P<；0.05)显著相关。表达下调和过表达的胃癌细胞系细胞的增殖、迁移和侵袭分别显著减少和增加(P<；0.05)。在MKN74和MKN45细胞中敲除SETDB2后，全球H3K9三甲基化(ME3)水平降低。基因芯片分析表明，SETDB2DNA被敲除后，抑癌基因WWOX和CADM1在MKN74细胞中的表达显著增强。染色质免疫沉淀分析表明，这两个基因启动子区域的H3K9me3水平与胃癌细胞中SETDB2mRNA的表达水平相对应。此外，异位的SETDB2蛋白被招募到它们的启动子区域。我们的数据表明，SETDB2与WWOX和CADM1的转录抑制有关，因此SETDB2超表达可能有助于GC的进展。
SETDB2 is a histone H3 lysine 9 (H3K9) tri-methyltransferase that is involved in transcriptional gene silencing. Since it is still unknown whether SETDB2 is linked to carcinogenesis, we studied alterations and functions of SETDB2 in human gastric cancers (GCs). SETDB2 protein was highly expressed in 30 of 72 (41.7%) primary GC tissues compared with their normal counterparts by immunohistochemistry. SETDB2 overexpression was significantly associated with the late stage of GCs (P<0.05) and poor prognosis of GC patients (P<0.05). The GC cell lines with SETDB2 knockdown and overexpression significantly decreased and increased cell proliferation, migration and invasion, respectively (P<0.05). Knockdown of SETDB2 in MKN74 and MKN45 cells reduced global H3K9 tri-methylation (me3) levels. Microarray analysis indicated that expression of WWOX and CADM1, tumor suppressor genes, was significantly enhanced in MKN74 cells after SETDB2 knockdown. Chromatin immunoprecipitation assays showed that the H3K9me3 levels at the promoter regions of these two genes corresponded to the SETDB2 expression levels in GC cells. Moreover, ectopic SETDB2 protein was recruited to their promoter regions. Our data suggest that SETDB2 is associated with transcriptional repression of WWOX and CADM1, and hence overexpression of SETDB2 may contribute to GC progression.