Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription
Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription
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Menin 促进肝细胞癌变并在表观遗传上上调 Yap1 转录。
DOI：
10.1073/pnas.1312022110
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发表时间：
2013-10-22
影响因子：
11.1
通讯作者：
Jin, Guang-Hui
中科院分区：
文献类型：
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作者：
Xu, Bin;Li, Shan-Hua;Jin, Guang-Hui
表观遗传学改变常发生在肝细胞癌（HCC）中，并与异常基因表达相关。大多数研究都集中在表观遗传基因沉默事件;因此，促进HCC中基因激活的机制尚未完全建立。我们确定了一种表观遗传激活机制，menin促进Yap 1转录，这与肝癌患者预后不良有关。脑膜炎混合系白血病复合体的大量过度表达与HCC中肿瘤启动子某些位点的组蛋白3赖氨酸4三甲基化增加相关小鼠多发性内分泌瘤1型（Men 1）杂合消融减少二乙基亚硝胺诱导的HCC发展我们的研究结果表明，menin在上调Yap 1转录，导致肝脏肿瘤发生中起着重要的表观遗传作用。Menin是由人类多发性内分泌瘤1型（MEN 1）基因编码的支架蛋白，它与多种转录蛋白相互作用以控制活性或抑制性细胞过程。在这里，我们表明，在雌性小鼠中Men 1的杂合消融减少了化学致癌物诱导的肝癌发生，并抑制了炎症通路的激活。使用ChIP芯片筛选和ChIP检测，我们发现menin占用经常与许多肝癌相关基因（如Yap 1）的启动子H3 K4 me 3相一致。人肝细胞癌标本中menin和Yap 1表达增加与预后不良相关。我们的研究结果表明，menin在促进肝脏肿瘤发生中起着重要的表观遗传作用，并支持由menin-mixed-lineage leukemia complex调控的H3 K4 me 3是肝细胞癌潜在治疗靶点的观点。
Significance Epigenetic changes commonly occur in hepatocellular carcinoma (HCC) and are associated with aberrant gene expression. Most studies have focused on epigenetic gene-silencing events; therefore, the mechanism that promotes gene activation in HCC is not well established. We identify an epigenetic activation mechanism whereby menin promotes Yes-associated protein (Yap1) transcription, which is associated with a poor prognosis for HCC patients. Substantial overexpression of the menin–mixed-lineage leukemia complex is associated with increased histone 3 lysine 4 trimethylation at certain loci of the tumor promoter in HCC. Heterozygous ablation of multiple endocrine neoplasia type 1 (Men1) in mice reduces diethylnitrosamine-induced development of HCC. Our findings reveal that menin plays an important epigenetic role in up-regulating Yap1 transcription, leading to liver tumorigenesis. Menin is a scaffold protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene in humans, and it interacts with a variety of transcriptional proteins to control active or repressive cellular processes. Here, we show that heterozygous ablation of Men1 in female mice reduces chemical carcinogen-induced liver carcinogenesis and represses the activation of the inflammation pathway. Using ChIP-on-chip screens and ChIP assays, we find that menin occupancy frequently coincides with H3K4me3 at the promoter of many liver cancer-related genes, such as Yes-associated protein (Yap1). Increased menin and Yap1 expression in human hepatocellular carcinoma specimens was associated with poor prognosis. Our findings reveal that menin plays an important epigenetic role in promoting liver tumorigenesis, and support the notion that H3K4me3, which is regulated by the menin–mixed-lineage leukemia complex, is a potential therapeutic target in hepatocellular carcinoma.