SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression
SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression
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SETDB1通过上调CCND1和MMP9表达促进胃癌发生和转移
DOI：
10.1002/path.5568
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发表时间：
2020-11-18
影响因子：
7.3
通讯作者：
Jia, Jihui
中科院分区：
文献类型：
--
作者：
Shang, Wenjing;Wang, Yue;Jia, Jihui
SETDB1是一种组蛋白赖氨酸甲基转移酶，在癌症中起关键作用。然而，它在胃癌(GC)中的潜在作用仍不清楚。在这里，我们主要探讨SETDB1在胃癌中的临床意义和可能的作用。我们发现SETDB1在胃癌组织中表达上调，其高水平表达是患者预后不良的预测指标。SETDB1过表达促进了细胞的增殖和转移，而抑制SETDB1在体内和体外的作用则相反。机制上，SETDB1与ERG相互作用，通过结合细胞周期蛋白D1(CCND1)和基质金属蛋白酶9(MMP9)的启动子区域，促进其转录。此外，转录因子TCF4也在转录水平上促进了SETDB1在胃癌中的表达。此外，还发现SETDB1的表达是由幽门螺杆菌感染以TCF4依赖的方式诱导的。综上所述，我们的结果表明，SETDB1在胃癌中异常过表达，并通过上调CCND1和MMP9在胃癌的发生和转移中发挥关键作用。我们的工作还表明，SETDB1可能是一个潜在的致癌因子和GC的治疗靶点。(C)2020年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
SETDB1 is a histone lysine methyltransferase that has critical roles in cancers. However, its potential role in gastric cancer (GC) remains obscure. Here, we mainly investigate the clinical significance and the possible role of SETDB1 in GC. We find that SETDB1 expression is upregulated in GC tissues and its high-level expression was a predictor of poor prognosis in patients. Overexpression of SETDB1 promoted cell proliferation and metastasis, while SETDB1 suppression had an opposite effect both in vitro and in vivo. Mechanistically, SETDB1 was shown to interact with ERG to promote the transcription of cyclin D1 (CCND1) and matrix metalloproteinase 9 (MMP9) through binding to their promoter regions. In addition, the expression of SETDB1 was also enhanced by the transcription factor TCF4 at the transcriptional level in GC. Furthermore, SETDB1 expression was found to be induced by Helicobacter pylori (H. pylori) infection in a TCF4-dependent manner. Taken together, our results indicate that SETDB1 is aberrantly overexpressed in GC and plays key roles in gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9. Our work also suggests that SETDB1 could be a potential oncogenic factor and a therapeutic target for GC. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.