Polycomb repressor complex-2 is a novel target for mesothelioma therapy.
Polycomb repressor complex-2 is a novel target for mesothelioma therapy.
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DOI：
10.1158/1078-0432.ccr-11-0962
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Schrump DS
中科院分区：
文献类型：
--
作者：
Kemp CD;Rao M;Xi S;Inchauste S;Mani H;Fetsch P;Filie A;Zhang M;Hong JA;Walker RL;Zhu YJ;Ripley RT;Mathur A;Liu F;Yang M;Meltzer PA;Marquez VE;De Rienzo A;Bueno R;Schrump DS
Polycomb group (PcG) proteins are critical epigenetic mediators of stem cell pluripotency, which have been implicated in the pathogenesis of human cancers. The present study was undertaken to examine the frequency and clinical relevance of PcG protein expression in malignant pleural mesotheliomas (MPM). Microarray, quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry techniques were used to examine PcG protein expression in cultured MPM, mesothelioma specimens, and normal mesothelial cells. Lentiviral shRNA techniques were used to inhibit EZH2 and EED expression in MPM cells. Proliferation, migration, clonogenicity and tumorigenicity of MPM cells either exhibiting knock-down of EZH2 or EED, or exposed to 3-deazaneplanocin A (DZNep), and respective controls were assessed by cell count, scratch and soft agar assays, and murine xenograft experiments. Micro-array and qRT-PCR techniques were used to examine gene expression profiles mediated by knock-down of EZH2 or EED, or DZNep. EZH2 and EED, which encode components of polycomb repressor complex 2 (PRC-2), were over-expressed in MPM lines relative to normal mesothelial cells. EZH2 was over-expressed in ~85% of MPMs compared to normal pleura, correlating with diminished patient survival. Over-expression of EZH2 coincided with decreased levels of miR-101 and miR-26a. Knock-down of EZH2 or EED, or DZNep treatment decreased global H3K27Me3 levels, and significantly inhibited proliferation, migration, clonogenicity, and tumorigenicity of MPM cells. Common as well as differential gene expression profiles were observed following knock-down of PRC-2 members or DZNep treatment. Pharmacologic inhibition of PRC-2 expression/activity is a novel strategy for mesothelioma therapy.
