Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer
Genome-Wide Identification of PAX3-FKHR Binding Sites in Rhabdomyosarcoma Reveals Candidate Target Genes Important for Development and Cancer
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DOI：
10.1158/0008-5472.can-10-0582
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发表时间：
2010-08-15
期刊：
影响因子：
11.2
通讯作者：
Meltzer, Paul S.
中科院分区：
文献类型：
--
作者：
Cao, Liang;Yu, Yunkai;Meltzer, Paul S.
PAX 3-FKHR融合蛋白存在于大多数与侵袭性增加和预后不良相关的肺泡型横纹肌肉瘤中。为了更好地了解PAX 3-FKHR的分子发病机制，我们对肺泡横纹肌肉瘤中的PAX 3-FKHR结合位点和相关靶基因进行了首次、公正的全基因组鉴定。数据显示PAX 3-FKHR在MYF 5和MYOD增强子处与PAX 3结合相同的位点。全基因组分析显示PAX 3-FKHR位点（a）大多数位于转录起始位点的远端，（B）保守，（c）富含PAX 3基序，（d）与PAX 3-FKHR阳性横纹肌肉瘤细胞和肿瘤中过表达的基因密切相关。在我们的数据集中几乎没有PAX 3-FKHR在启动子序列处结合的证据。全基因组分析进一步说明了PAX 3和E-box基序在这些结合位点之间的强烈关联，表明许多靶基因存在共同的共调控。我们还提供了第一个直接证据表明FGFR 4和IGF 1 R是PAX 3-FKHR的靶点。PAX 3-FKHR结合位点的图谱为理解PAX 3-FKHR的致病作用及其分子靶点提供了一个框架，从而可以系统地评价针对这种侵袭性横纹肌肉瘤的药物。Cancer Res; 70（16）; 6497-508.（C）2010年AACR。
The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR-positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma. Cancer Res; 70(16); 6497-508. (C)2010 AACR.