Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK-3β/β-catenin signaling.
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 β-catenin was overexpressed in OS tissue, and that knockdown of β-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-3β/β-catenin signaling pathway by using pharmacological inhibitor GSK-3β (LiCl) or siGSK-3β. Our findings reveal a novel mechanism that Runx2 is transcriptionally regulated by HSP90 via the AKT/GSK-3β/β-catenin signaling pathway, and by which leads to apoptosis of OS cells.
['Liang|Gui-Hong|GH|', 'Liu|Ning|N|', 'He|Ming-Tang|MT|', 'Yang|Jie|J|', 'Liang|Zu-Jian|ZJ|', 'Gao|Xue-Juan|XJ|', 'Rahhal|Ali Hasan|AH|', 'He|Qing-Yu|QY|', 'Zhang|Huan-Tian|HT|0000-0002-7391-436X', 'Zha|Zhen-Gang|ZG|']
D016227:Benzoquinones D001859:Bone Neoplasms D045744:Cell Line, Tumor D002470:Cell Survival D050659:Core Binding Factor Alpha 1 Subunit D015972:Gene Expression Regulation, Neoplastic D000071679:Glycogen Synthase Kinase 3 beta D018841:HSP90 Heat-Shock Proteins D006801:Humans D047029:Lactams, Macrocyclic D007976:Leupeptins D012516:Osteosarcoma D051057:Proto-Oncogene Proteins c-akt D015398:Signal Transduction D014158:Transcription, Genetic D051176:beta Catenin
RUNX2 osteosarcoma apoptosis β-catenin 17-AAG heat shock protein 90