Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression.
Reduced expression of SET7/9, a histone mono-methyltransferase, is associated with gastric cancer progression.
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DOI：
10.18632/oncotarget.6681
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发表时间：
2016-01-26
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：
Akiyama Y;Koda Y;Byeon SJ;Shimada S;Nishikawaji T;Sakamoto A;Chen Y;Kojima K;Kawano T;Eishi Y;Deng D;Kim WH;Zhu WG;Yuasa Y;Tanaka S
SET 7/9是一种组蛋白甲基转移酶，对赖氨酸甲基化有两种不同的功能。SET 7/9甲基化非组蛋白蛋白，如p53，并参与其翻译后修饰。尽管SET 7/9通过H3 K4单甲基化转录激活基因，但其靶基因知之甚少。为了阐明SET 7/9是否与胃癌发生有关，我们研究了胃癌（GC）中SET 7/9的变化。在376例原发性胃癌组织中，129例（34.3%）与相应的癌旁组织相比，SET 7/9蛋白表达缺失或弱表达。SET 7/9表达降低与临床侵袭性和预后不良显著相关。胃癌细胞中SET 7/9的敲低显著增加了细胞的增殖、迁移和侵袭。SET 7/9基因敲减后，胃癌细胞SREK 1 IP 1、PGC和CCDC 28 B的表达受到抑制，而基质金属蛋白酶基因（MMP 1、MMP 7和MMP 9）则被激活。SET 7/9在SREK 1 IP 1转录起始位点上游约4-6 kb区域以及PGC和CDC 28 B的启动子处结合并单甲基化H3 K4。SREK 1 IP基因敲低组胃癌细胞的增殖、迁移和侵袭能力以及3种MMPs的表达均增强，与SET 7/9基因敲低组相似。这些数据表明，SET 7/9具有肿瘤抑制功能，并且SET 7/9的缺失可能有助于胃癌的进展。
SET7/9, a histone methyltransferase, has two distinct functions for lysine methylation. SET7/9 methylates non-histone proteins, such as p53, and participates in their posttranslational modifications. Although SET7/9 transcriptionally activate the genes via H3K4 mono-methylation, its target genes are poorly understood. To clarify whether or not SET7/9 is related to carcinogenesis, we studied alterations of SET7/9 in gastric cancers (GCs). Among the 376 primary GCs, 129 cases (34.3%) showed loss or weak expression of SET7/9 protein compared to matched non-cancerous tissues by immunohistochemistry. Reduced SET7/9 expression was significantly correlated with clinical aggressiveness and worse prognosis. Knockdown of SET7/9 in GC cells markedly increased cell proliferation, migration and invasion. Expression of SREK1IP1, PGC and CCDC28B were inhibited in GC cells with SET7/9 knockdown, while matrix metalloproteinase genes (MMP1, MMP7 and MMP9) were activated. SET7/9 bound and mono-methylated H3K4 at the region of the approximately 4-6 kb upstream from the SREK1IP1 transcriptional start site and the promoters of PGC and CDC28B. Cell proliferation, migration and invasion, and expression of three MMPs were increased in GC cells with SREK1IP knockdown, which were similar to those of SET7/9 knockdown. These data suggest that SET7/9 has tumor suppressor functions, and loss of SET7/9 may contribute to gastric cancer progression.