The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis
The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis
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DOI：
10.1158/0008-5472.can-10-2695
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Fujita, Naoya
中科院分区：
文献类型：
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作者：
Nakazawa, Youya;Arai, Hiroyuki;Fujita, Naoya
了解转移是治愈性癌症治疗不可或缺的一部分。通过小鼠遗传筛选模型，我们发现Merm1/Wbscr22是一种新的转移启动子，其结构中包含一个甲基转移酶折叠。Merm1在浸润性乳腺癌中表现出高水平表达。Merm1在非转移性细胞中的异位表达增强了转移的形成，而不影响细胞的生长和运动。Merm1完整的甲基转移酶折叠是转移形成所必需的。有趣的是，Merm1的表达促进了被困在肺微血管中的细胞存活。与这些结果一致，肿瘤细胞中内源性Merm1的敲除减少了肺潴留和转移的形成。在比较转录组分析的基础上，Merm1的表达与肿瘤抑制因子Zac1的表达呈负相关。我们证实，在Zac1启动子区域的Lys(9)处，Merm1通过组蛋白H3甲基化抑制Zac1的表达。Zac1可以通过转录共激活p53来诱导细胞凋亡，而p53调节血管中的细胞凋亡，在转移过程中经常下调。我们发现Zac1敲低降低了p53依赖性细胞凋亡，而Merm1敲低增强了p53依赖性细胞凋亡，从而增加了转移细胞的肺潴留。我们的研究结果表明，Merm1通过抑制Zac1/p53依赖的细胞凋亡，从而增强肿瘤细胞在血管中的存活，从而促进转移。癌症Res;71 (3);1146 - 55。(c) 2010年aacr。
Understanding metastasis is integral to curative cancer treatments. Using a mouse genetic screening model, we identified Merm1/Wbscr22 as a novel metastasis promoter that includes a methyltransferase fold in its structure. Merm1 showed high levels of expression in invasive breast cancer. Ectopic expression of Merm1 in nonmetastatic cells enhanced metastasis formation without affecting cell growth and motility. The intact methyltransferase fold of Merm1 was required for metastasis formation. Interestingly, Merm1 expression promoted cell survival after entrapment in the lung microvasculature. Consistent with these results, knockdown of endogenous Merm1 in tumor cells reduced lung retention and metastasis formation. On the basis of comparative transcriptome analysis, Merm1 expression was negatively correlated with the expression of tumor suppressor Zac1. We confirmed that Merm1 suppressed Zac1 expression with histone H3 methylation at Lys(9) in the Zac1 promoter region. Zac1 can induce apoptosis through its ability to transcriptionally coactivate p53, which regulates apoptosis in the vasculature and is often downregulated in metastasis. We found that Zac1 knockdown reduced the p53-dependent apoptosis that was enhanced by Merm1 knockdown, thereby increasing lung retention of metastatic cells. Our findings show that Merm1 enhances cancer cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis, thereby enhancing metastasis. Cancer Res; 71( 3); 1146-55. (C) 2010 AACR.