Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma
Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma
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DOI：
10.7554/elife.19214
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发表时间：
2017-01-12
期刊：
影响因子：
7.7
通讯作者：
Langenau, David M.
中科院分区：
文献类型：
--
作者：
Tenente, Ines M.;Hayes, Madeline N.;Langenau, David M.
横纹肌肉瘤（Rhabdomyosarcoma， RMS）是一种小儿肌肉恶性肿瘤，在该病中表达肌原性调节转录因子MYOD和MYF5。该领域的共识是，这些因子的表达可能反映了转化的靶细胞，而不是肿瘤持续生长所必需的。在这里，我们使用转基因斑马鱼模型来证明Myf5足以赋予RMS细胞肿瘤增殖潜能，并导致肿瘤更早启动，具有更高的外显率。对人类RMS的分析显示，MYF5和MYOD是相互排斥表达的，每一个都是肿瘤持续生长所必需的。人类RMS的ChIP-seq和机制研究发现，MYF5和MYOD结合共同的DNA调控元件，改变调节肌肉发育和细胞周期进展的基因的转录。我们的数据支持MYF5和MYOD聚集在共同转录靶标上调控人类RMS生长的未被重视的显性致癌作用。
Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.