The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)
The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)
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DOI：
10.1038/onc.2013.471
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发表时间：
2014-08-07
期刊：
影响因子：
8
通讯作者：
Rota, R.
中科院分区：
文献类型：
--
作者：
Ciarapica, R.;De Salvo, M.;Rota, R.
Polycomb蛋白群（Polycomb group, PcG）通过抑制基因转录来调节干细胞的分化，其失调已被广泛地认为与癌症的发生有关。Zeste Homolog 2的PcG蛋白增强子（EZH2）作为多梳抑制复合物2 （PRC2）的催化亚基，通过甲基化组蛋白H3 （H3K27me3）上的赖氨酸27，这是PRC2介导的基因抑制的标志。在骨骼肌祖细胞中，EZH2通过抑制肌肉特异性基因表达来阻止计划外分化，并在分化过程中下调。横纹肌肉瘤（rhabdomyosarcoma， RMS）是一种小儿软组织肉瘤，被认为起源于肌源性前体，EZH2在体外异常表达，其下调导致胚胎变异的横纹肌肉瘤细胞向肌肉样分化。然而，EZH2在肺泡RMS临床侵袭性亚组（以PAX3-FOXO1癌蛋白表达为特征）中的作用尚不清楚。我们在这里表明，EZH2在这些细胞中耗竭导致程序性细胞死亡。在EZH2沉默的PAX3-FOXO1 RMS细胞中，与肌肉稳态相关的基因F-box蛋白32 (FBXO32) （Atrogin1/MAFbx）的转录抑制被证实。这种现象与FBXO32启动子上EZH2占用率和H3K27me3水平的降低有关。在PAX3-FOXO1 RMS细胞中，同时敲低FBXO32和EZH2可抑制促凋亡反应，而过表达FBXO32可促进EZH2缺失细胞的程序性死亡。3-Deazaneplanocin A或催化性EZH2抑制剂对EZH2的药理抑制在体外反映了EZH2敲除的表型和分子效应，并在体内阻止了肿瘤的生长。综上所述，这些结果表明EZH2是PAX3-FOXO1肺泡RMS细胞增殖和存活的关键因素，至少部分通过抑制FBXO32起作用。他们还认为，EZH2的活性降低可能是一种新的辅助策略，可以根除高风险的PAX3-FOXO1肺泡RMS。
The Polycomb group (PcG) proteins regulate stem cell differentiation via the repression of gene transcription, and their deregulation has been widely implicated in cancer development. The PcG protein Enhancer of Zeste Homolog 2 (EZH2) works as a catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) by methylating lysine 27 on histone H3 (H3K27me3), a hallmark of PRC2-mediated gene repression. In skeletal muscle progenitors, EZH2 prevents an unscheduled differentiation by repressing muscle-specific gene expression and is downregulated during the course of differentiation. In rhabdomyosarcoma (RMS), a pediatric soft-tissue sarcoma thought to arise from myogenic precursors, EZH2 is abnormally expressed and its downregulation in vitro leads to muscle-like differentiation of RMS cells of the embryonal variant. However, the role of EZH2 in the clinically aggressive subgroup of alveolar RMS, characterized by the expression of PAX3-FOXO1 oncoprotein, remains unknown. We show here that EZH2 depletion in these cells leads to programmed cell death. Transcriptional derepression of F-box protein 32 (FBXO32) (Atrogin1/MAFbx), a gene associated with muscle homeostasis, was evidenced in PAX3-FOXO1 RMS cells silenced for EZH2. This phenomenon was associated with reduced EZH2 occupancy and H3K27me3 levels at the FBXO32 promoter. Simultaneous knockdown of FBXO32 and EZH2 in PAX3-FOXO1 RMS cells impaired the pro-apoptotic response, whereas the overexpression of FBXO32 facilitated programmed cell death in EZH2-depleted cells. Pharmacological inhibition of EZH2 by either 3-Deazaneplanocin A or a catalytic EZH2 inhibitor mirrored the phenotypic and molecular effects of EZH2 knockdown in vitro and prevented tumor growth in vivo. Collectively, these results indicate that EZH2 is a key factor in the proliferation and survival of PAX3-FOXO1 alveolar RMS cells working, at least in part, by repressing FBXO32. They also suggest that the reducing activity of EZH2 could represent a novel adjuvant strategy to eradicate high-risk PAX3-FOXO1 alveolar RMS.