Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma
Runx3 is required for oncogenic Myc upregulation in p53-deficient osteosarcoma
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DOI：
10.1038/s41388-021-02120-w
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发表时间：
2021-11-22
期刊：
影响因子：
8
通讯作者：
Ito, Kosei
中科院分区：
文献类型：
--
作者：
Otani, Shohei;Date, Yuki;Ito, Kosei
人类骨肉瘤（OS）的特征是TP 53基因的改变。骨祖细胞特异性p53基因缺失小鼠（Osteoprogenitor-specific p53-deleted mice，OS mice）已被广泛应用于研究骨肉瘤的发生过程。然而，在p53失活后，OS的发展的分子机制仍然在很大程度上未知。在这项研究中，我们检测到显着的RUNX 3/Runx 3表达在人类和小鼠p53缺陷的OS。Myc是异常上调Runx 3通过mR 1，在Myc启动子的共识Runx网站，在依赖于p53缺陷的方式。通过破坏mR 1或Runx 3敲低降低Myc水平可降低p53缺陷型OS细胞的致瘤性，并有效抑制OS小鼠的OS发展。此外，Runx抑制剂对OS小鼠具有治疗作用。总之，这些结果表明，p53缺陷通过允许Runx 3诱导致癌Myc表达而促进人和小鼠中的骨肉瘤comagenesis。
Osteosarcoma (OS) in human patients is characterized by genetic alteration of TP53. Osteoprogenitor-specific p53-deleted mice (OS mice) have been widely used to study the process of osteosarcomagenesis. However, the molecular mechanisms responsible for the development of OS upon p53 inactivation remain largely unknown. In this study, we detected prominent RUNX3/Runx3 expression in human and mouse p53-deficient OS. Myc was aberrantly upregulated by Runx3 via mR1, a consensus Runx site in the Myc promoter, in a manner dependent on p53 deficiency. Reduction of the Myc level by disruption of mR1 or Runx3 knockdown decreased the tumorigenicity of p53-deficient OS cells and effectively suppressed OS development in OS mice. Furthermore, Runx inhibitors exerted therapeutic effects on OS mice. Together, these results show that p53 deficiency promotes osteosarcomagenesis in human and mouse by allowing Runx3 to induce oncogenic Myc expression.