TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle.
TBX2 represses PTEN in rhabdomyosarcoma and skeletal muscle.
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DOI：
10.1038/onc.2015.486
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发表时间：
2016-08-11
期刊：
影响因子：
8
通讯作者：
Davie JK
中科院分区：
文献类型：
--
作者：
Zhu B;Zhang M;Williams EM;Keller C;Mansoor A;Davie JK
横纹肌肉瘤（RMS）是儿童最常见的软组织肉瘤，具有许多骨骼肌发育的特征。TBX 2是一个T-box家族成员，在两种主要RMS亚型的肿瘤细胞中高度上调，其中它作为致癌基因发挥作用。TBX 2是一种阻遏物，通常在癌细胞中过度表达，并在绕过细胞生长控制中发挥作用，包括细胞周期调节因子p14和p21的阻遏。我们已经发现TBX 2直接抑制RMS和正常肌肉中的肿瘤抑制因子PTEN。正常肌肉细胞中TBX 2的外源性表达下调PTEN，RMS细胞中TBX 2的缺失或干扰上调PTEN。人RMS肿瘤显示高水平的TBX 2和相应的低水平的PTEN。临床RMS样本中PTEN的表达相对不明确，我们确定PTEN的抑制在RMS的两种亚型中是常见的事件。TBX 2通过直接与启动子结合并募集组蛋白脱乙酰酶HDAC 1来抑制PTEN。RMS细胞由于PI 3 K信号传导的失调而具有高水平的活化AKT，并且耗尽或干扰上调PTEN的TBX 2导致磷酸化AKT的减少。我们还发现，高度相关的T-box家族成员TBX 3在肌肉谱系中不抑制PTEN。这项工作表明，TBX 2是RMS细胞中PTEN/PI 3 K/AKT信号通路失调的核心组成部分，并且在RMS肿瘤中靶向TBX 2可能为RMS提供新的治疗方法。
Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children that shares many features of developing skeletal muscle. TBX2, a T-box family member, is highly up regulated in tumor cells of both major RMS subtypes where it functions as an oncogene. TBX2 is a repressor that is often over expressed in cancer cells and functions in bypassing cell growth control, including the repression of the cell cycle regulators p14 and p21. We have found that TBX2 directly represses the tumor suppressor PTEN in both RMS and normal muscle. Exogenous expression of TBX2 in normal muscle cells down regulates PTEN, and depletion or interference with TBX2 in RMS cells up regulates PTEN. Human RMS tumors show high levels of TBX2 and correspondingly low levels of PTEN. The expression of PTEN in clinical RMS samples is relatively uncharacterized and we establish that suppression of PTEN is a frequent event in both subtypes of RMS. TBX2 represses PTEN by directly binding to the promoter and recruiting the histone deacetylase, HDAC1. RMS cells have high levels of activated AKT due to the deregulation of PI3K signaling, and depletion or interference with TBX2, which up regulates PTEN, results in a reduction of phospho-AKT. We have also found that the highly related T-box family member TBX3 does not repress PTEN in the muscle lineage. This work suggests that TBX2 is a central component of the PTEN/PI3K/AKT signaling pathway deregulation in RMS cells and that targeting TBX2 in RMS tumors may offer a novel therapeutic approach for RMS.