Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK-3/-catenin signaling
Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK-3/-catenin signaling
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HSP90 对 Runx2 的转录调节通过 AKT/GSK-3/-catenin 信号传导控制骨肉瘤细胞凋亡
DOI：
10.1002/jcb.26260
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Zha, Zhen-Gang
中科院分区：
文献类型：
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作者：
Liang, Gui-Hong;Liu, Ning;Zha, Zhen-Gang
骨肉瘤（OS）是儿童和青少年最恶性的原发性骨肿瘤，治疗选择有限，预后差。近年来发现Runx 2在OS中异常表达，从而促进了OS的发生、发展，但其上游信号分子在OS中的表达调控机制尚不清楚。在本研究中，我们首先证实了用17-AAG抑制HSP 90通过caspase-3依赖的机制引起OS细胞的显著凋亡，并且通过17-AAG或siRNA抑制或敲低HSP 90显著抑制Runx 2的mRNA和蛋白表达。此外，我们提供的证据表明，Runx 2的转录调控HSP 90时，使用MG 132和CHX追逐试验。我们还表明，β-catenin在OS组织中过表达，并且在存在或不存在17-AAG的情况下，β-catenin的敲低诱导OS细胞的明显凋亡。有趣的是，这种现象伴随着Runx 2和Cyclin D1表达的显著降低，表明Runx 2/Cyclin D1在17-AAG诱导的细胞凋亡中起重要作用。此外，我们证明了17-AAG诱导的OS细胞凋亡确实需要AKT/GSK-3/β-catenin信号通路的参与，通过使用药理学抑制剂GSK-3（LiCl）或siGSK-3。我们的研究结果揭示了Runx 2通过AKT/GSK-3/β-catenin信号通路被HSP 90转录调控，从而导致OS细胞凋亡的新机制。
Osteosarcoma (OS) is the most malignant primary bone tumor in children and adolescents with limited treatment options and poor prognosis. Recently, aberrant expression of Runx2 has been found in OS, thereby contributing to the development, and progression of OS. However, the upstream signaling molecules that regulate its expression in OS remain largely unknown. In the present study, we first confirmed that the inhibition of HSP90 with 17-AAG caused significant apoptosis of OS cells via a caspase-3-dependent mechanism, and that inhibition or knockdown of HSP90 by 17-AAG or siRNAs significantly suppressed mRNA and protein expression of Runx2. Furthermore, we provided evidence that Runx2 was transcriptionally regulated by HSP90 when using MG132 and CHX chase assay. We also demonstrated that -catenin was overexpressed in OS tissue, and that knockdown of -catenin induced pronounced apoptosis of OS cells in the presence or absence of 17-AAG. Interestingly, this phenomenon was accompanied with a significant reduction of Runx2 and Cyclin D1 expression, indicating an essential role of Runx2/Cyclin D1 in 17-AAG-induced cells apoptosis. Moreover, we demonstrated that the apoptosis of OS cells induced by 17-AAG did require the involvement of the AKT/GSK-3/-catenin signaling pathway by using pharmacological inhibitor GSK-3 (LiCl) or siGSK-3. Our findings reveal a novel mechanism that Runx2 is transcriptionally regulated by HSP90 via the AKT/GSK-3/-catenin signaling pathway, and by which leads to apoptosis of OS cells.