Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.
Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.
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组蛋白甲基转移酶 SET8 受 miR-192/215 调节，并通过人胃癌细胞中 p53 依赖性 DNA 损伤诱导癌基因诱导的衰老
DOI：
10.1038/s41419-020-03130-4
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发表时间：
2020-10-30
影响因子：
9
通讯作者：
Jin Z
中科院分区：
文献类型：
--
作者：
Zhang X;Peng Y;Yuan Y;Gao Y;Hu F;Wang J;Zhu X;Feng X;Cheng Y;Wei Y;Fan X;Xie Y;Lv Y;Ashktorab H;Smoot D;Li S;Meltzer SJ;Hou G;Jin Z
胃癌（GC）是世界上最常见的癌症。尽管治疗取得了进展，但详细的致癌机制在很大程度上是未知的。在我们之前的研究中，我们使用miR微阵列研究了人GC中的microRNA （miR）表达谱。我们发现miR-192/215在GC组织中上调。然后利用基因芯片技术发现miR-192/215的靶点。我们分别比较了转染miR-192/215抑制剂的BGC823细胞和转染miR-192/-215模拟物的HFE145细胞的表达谱。基于两倍以上的表达变化，将SET8确定为提议的靶标。SET8属于SET结构域甲基转移酶家族，特异催化H4K20me的单甲基化。它在肿瘤发生和转移过程中参与多种功能。因此，我们关注miR-192/215/SET8轴对GC发展的贡献。在本研究中，我们观察到miR-192/215调控的SET8在功能上参与了gc相关的生物活性。在体内和体外实验中，SET8也被发现在GC中触发癌基因诱导的衰老（OIS），这依赖于DDR （DNA损伤反应）和p53。我们的研究结果表明，SET8通过ois信号通路作为转移的负调节因子。综上所述，我们研究了miR-192/215/SET8/p53在胃癌中的功能意义、分子机制和临床影响。
Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
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