Zhu B, Zhang M, Williams E M, Keller C, Mansoor A, Davie J K
Department of Biochemistry and Molecular Biology and Simmons Cancer Institute, Southern Illinois University School of Medicine, Carbondale, IL, USA.
Department of Pathology, Oregon Health and Sciences University, Portland, OR, USA.
Oncogene. 2016 Aug 11;35(32):4212-24. doi: 10.1038/onc.2015.486. Epub 2015 Dec 21.
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 upregulated in tumor cells of both major RMS subtypes where it functions as an oncogene. TBX2 is a repressor that is often overexpressed 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 phosphatase and tensin homolog (PTEN) in both RMS and normal muscle. Exogenous expression of TBX2 in normal muscle cells downregulates PTEN, and depletion or interference with TBX2 in RMS cells upregulates 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 owing to the deregulation of phosphoinositide-3 kinase (PI3K) signaling, and depletion or interference with TBX2, which upregulates 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.
横纹肌肉瘤（RMS）是儿童中最常见的软组织肉瘤，具有许多发育中骨骼肌的特征。TBX2是T-box家族成员，在两种主要RMS亚型的肿瘤细胞中高度上调，发挥癌基因的作用。TBX2是一种阻遏物，在癌细胞中常过度表达，在绕过细胞生长控制中起作用，包括抑制细胞周期调节因子p14和p21。我们发现，TBX2在RMS和正常肌肉中均直接抑制肿瘤抑制因子磷酸酶和张力蛋白同源物（PTEN）。在正常肌肉细胞中外源表达TBX2会下调PTEN，而在RMS细胞中耗尽或干扰TBX2则会上调PTEN。人类RMS肿瘤显示出高水平的TBX2和相应低水平的PTEN。PTEN在临床RMS样本中的表达相对未被充分研究，我们确定PTEN的抑制在RMS的两种亚型中都是常见事件。TBX2通过直接结合启动子并募集组蛋白脱乙酰酶HDAC1来抑制PTEN。由于磷酸肌醇-3激酶（PI3K）信号失调，RMS细胞具有高水平的活化AKT，耗尽或干扰上调PTEN的TBX2会导致磷酸化AKT减少。我们还发现，高度相关的T-box家族成员TBX3在肌肉谱系中不抑制PTEN。这项工作表明，TBX2是RMS细胞中PTEN/PI3K/AKT信号通路失调的核心成分，在RMS肿瘤中靶向TBX2可能为RMS提供一种新的治疗方法。
