SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9.
SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9.
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DOI：
10.1158/0008-5472.can-11-1052
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Weitzman JB
中科院分区：
文献类型：
--
作者：
Cock-Rada AM;Medjkane S;Janski N;Yousfi N;Perichon M;Chaussepied M;Chluba J;Langsley G;Weitzman JB
基质金属蛋白酶MMP-9的上调通过刺激细胞迁移、肿瘤侵袭和血管生成在肿瘤进展和转移中起中心作用。为了深入了解MMP-9的表达，我们研究了其表观遗传控制在一个可逆的癌症模型，这是由感染细胞内泰勒虫寄生虫。寄生虫感染的基因诱导与MMP-9启动子处的组蛋白H3 K4（H3 K4 me 3）的三甲基化相关。值得注意的是，我们发现H3 K4甲基转移酶SMYD 3是感染后唯一上调的组蛋白甲基转移酶。SMYD 3在许多类型的癌细胞中过表达，但其对恶性病理生理学的贡献尚不清楚。我们发现SMYD 3的过度表达足以诱导转化的白细胞和纤维肉瘤细胞中MMP-9的表达，并且促炎佛波醇酯进一步增强了这种作用。此外，SMYD 3足以增加与MMP-9表达相关的细胞迁移。相比之下，RNAi介导的SMYD 3敲低降低了MMP-9启动子的H3 K4 me 3修饰，降低了MMP-9表达并降低了肿瘤细胞增殖。此外，SMYD 3敲低还减少了癌症的斑马鱼异种移植模型中的细胞侵袭。总之，我们的研究结果将SMYD 3定义为MMP-9转录的重要新调节因子，并且它们提供了SMYD 3过表达与转移性癌症进展之间的分子联系。
Upregulation of the matrix metalloproteinase MMP-9 plays a central role in tumor progression and metastasis by stimulating cell migration, tumor invasion and angiogenesis. To gain insights into MMP-9 expression, we investigated its epigenetic control in a reversible model of cancer that is initiated by infection with intracellular Theileria parasites. Gene induction by parasite infection was associated with tri-methylation of histone H3K4 (H3K4me3) at the MMP-9 promoter. Notably, we found that the H3K4 methyltransferase SMYD3 was the only histone methyltransferase upregulated upon infection. SMYD3 is overexpressed in many types of cancer cells, but its contributions to malignant pathophysiology are unclear. We found that overexpression of SMYD3 was sufficient to induce MMP-9 expression in transformed leukocytes and fibrosarcoma cells, and that pro-inflammatory phorbol esters further enhanced this effect. Further, SMYD3 was sufficient to increase cell migration associated with MMP-9 expression. In contrast, RNAi-mediated knockdown of SMYD3 decreased H3K4me3 modification of the MMP-9 promoter, reduced MMP-9 expression and reduced tumor cell proliferation. Furthermore, SMYD3 knockdown also reduced cellular invasion in a zebrafish xenograft model of cancer. Together, our results define SMYD3 as an important new regulator of MMP-9 transcription, and they provide a molecular link between SMYD3 overexpression and metastatic cancer progression.