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Transcriptional regulation of Runx2 by HSP90 controls osteosarcoma apoptosis via the AKT/GSK‐3β/β‐catenin signaling
Author(s) -
Liang GuiHong,
Liu Ning,
He MingTang,
Yang Jie,
Liang ZuJian,
Gao XueJuan,
Rahhal Ali Hasan,
He QingYu,
Zhang HuanTian,
Zha ZhenGang
Publication year - 2018
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.26260
Subject(s) - gene knockdown , protein kinase b , cyclin d1 , mg132 , apoptosis , survivin , cancer research , pi3k/akt/mtor pathway , hsp90 inhibitor , signal transduction , runx2 , small interfering rna , hsp90 , chemistry , microbiology and biotechnology , biology , cell cycle , cell culture , transcription factor , proteasome inhibitor , transfection , biochemistry , heat shock protein , genetics , gene
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.