HSP90 regulates osteosarcoma cell apoptosis by targeting the p53/TCF-1-mediated transcriptional network
HSP90 regulates osteosarcoma cell apoptosis by targeting the p53/TCF-1-mediated transcriptional network
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HSP90 通过靶向 p53/TCF-1 介导的转录网络调节骨肉瘤细胞凋亡
DOI：
10.1002/jcp.29283
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发表时间：
2019-10-09
影响因子：
5.6
通讯作者：
Zha, Zhen-Gang
中科院分区：
文献类型：
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作者：
Yang, Jie;Li, Yu-Hang;Zha, Zhen-Gang
骨肉瘤（OS）是最常见的骨肿瘤，主要发生在儿童和青少年。虽然许多基因，如p53和Rb 1，已被证明是突变的，但在OS中经常观察到经典Wnt/β-catenin信号通路的失调。我们最近证明，热休克蛋白90（HSP 90）通过AKT/GSK-3 β/β-catenin信号通路参与OS中runt相关转录因子2的调节。然而，T细胞因子/淋巴增强结合因子（TCF/LEF）家族成员是β-连环蛋白的主要结合复合物，其在OS中的确切作用知之甚少。在本研究中，我们首先证明了与其他骨肿瘤相比，TCF-1在OS中过表达。TCF-1的敲低显著诱导细胞周期停滞、严重的DNA损伤和随后的caspase-3依赖性凋亡。有趣的是，在OS中观察到HSP 90和TCF-1的共表达，并且从机制上讲，我们证明TCF-1的表达受HSP 90的调节，要么通过β-连环蛋白依赖性机制，要么通过蛋白酶体的直接降解。我们还发现TCF-1的过表达部分地消除了由HSP 90抑制诱导的凋亡。此外，我们提供的证据表明，p53，而不是miR-34 a，在热休克蛋白90调节的TCF-1表达和随后的凋亡中起着至关重要的作用。鉴于HSP 90抑制与其他治疗的不同组合方案，我们建议应考虑p53状态和TCF-1的表达水平，以提高HSP 90抑制的治疗效果。
Osteosarcoma (OS) is the most common bone tumor that occurs predominantly in children and teenagers. Although many genes, such as p53 and Rb1, have been shown to be mutated, deregulation of the canonical Wnt/beta-catenin signaling pathway is frequently observed in OS. We recently demonstrated that heat shock protein 90 (HSP90) is involved in the regulation of runt-related transcription factor 2 via the AKT/GSK-3 beta/beta-catenin signaling pathway in OS. However, the precise role of T cell factors/lymphoid enhancer-binding factor (TCFs/LEF) family members, which are the major binding complex of beta-catenin, in OS is poorly understood. In the present study, we first demonstrated that TCF-1 is overexpressed in OS compared with other bone tumors. Knockdown of TCF-1 significantly induced cell cycle arrest, severe DNA damage, and subsequent caspase-3-dependent apoptosis. Interestingly, coexpression of HSP90 and TCF-1 was observed in OS, and mechanistically, we demonstrated that TCF-1 expression is regulated by HSP90 either through a beta-catenin-dependent mechanism or a direct degradation of the proteasome. We also found that overexpression of TCF-1 partially abolishes the apoptosis induced by HSP90 inhibition. Furthermore, we provided evidence that p53, but not miR-34a, plays a crucial role in the HSP90-regulated TCF-1 expression and subsequent apoptosis. Given the diverse combination regimens of HSP90 inhibition with some other treatments, we propose that the p53 status and the expression level of TCF-1 should be taken into consideration to enhance the therapeutic efficacy of HSP90 inhibition.