The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.
The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial-mesenchymal transition and invasive properties of prostate cancer.
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DOI：
10.1038/onc.2012.297
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发表时间：
2013-06-06
期刊：
影响因子：
8
通讯作者：
Licht, J. D.
中科院分区：
文献类型：
--
作者：
Ezponda, T.;Popovic, R.;Shah, M. Y.;Martinez-Garcia, E.;Zheng, Y.;Min, D-J;Will, C.;Neri, A.;Kelleher, N. L.;Yu, J.;Licht, J. D.
基因表达的表观遗传失调在前列腺癌（PCa）的发生和发展中起作用。组蛋白甲基转移酶MMSET/WHSC 1（多发性骨髓瘤集结构域）在许多转移性肿瘤中过表达，但其作用机制尚未确定。在这项工作中，我们发现PCa细胞系表达的MMSET水平显著高于永生化的非转化前列腺细胞。敲除实验表明，在转移性前列腺癌细胞系中，组蛋白H3上赖氨酸36的二甲基化和赖氨酸27的三甲基化（分别为H3 K36 me 2和H3 K27 me 3）依赖于MMSET表达，而良性前列腺细胞中MMSET的耗尽不影响染色质修饰。DU 145和PC-3肿瘤细胞中MMSET的敲低降低了细胞增殖，软琼脂中的集落形成，并显著减少了细胞迁移和侵袭。相反，MMSET在永生化、非转化的RWPE-1细胞中的过表达促进了细胞迁移和侵袭，并伴有上皮向间充质转化（EMT）。在分析的一组EMT促进基因中，TWIST 1表达在MMSET反应中被强烈激活。染色质免疫沉淀分析表明，MMSET结合到TWIST 1位点，导致H3 K36 me 2的增加，表明MMSET在该基因的调节中的直接作用。在MMSET过表达RWPE-1细胞中TWIST 1的消耗阻断了细胞侵袭和EMT，表明TWIST 1是MMSET的关键靶标，负责获得侵袭性表型。总的来说，这些数据表明，MMSET通过转移相关基因的表观遗传调节在PCa发病机制和进展中发挥作用。
Epigenetic deregulation of gene expression plays a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma Set Domain) is overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared to immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, while depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar, and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial to mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus, leading to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET plays a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.
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影响因子：
14.8
作者：
Garcia, Benjamin A.;Mollah, Sahana;Hunt, Donald F.
通讯作者：
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DOI：
10.1016/j.bbrc.2008.12.093
发表时间：
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作者：
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