BIS-mediated STAT3 stabilization regulates glioblastoma stem cell-like phenotypes
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Chang-Nim Im1,2,3, Hye Hyeon Yun1,2, Byunghoo Song4, Dong-Ye Youn1, Mei Nu Cui1,2,3, Hong Sug Kim5, Gyeong Sin Park4,6, Jeong-Hwa Lee1,2,3
1Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea
2Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Korea
3Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
4Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea
5NGS Clinical Department, Macrogen Inc., Seoul, Korea
6Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
Jeong-Hwa Lee, email: [email protected]
Keywords: BIS, glioblastoma, CSCs, STAT3, ubiquitination
Received: January 22, 2016 Accepted: April 16, 2016 Published: April 27, 2016
Glioblastoma stem cells (GSCs) are a subpopulation of highly tumorigenic and stem-like cells that are responsible for resistance to conventional therapy. Bcl-2-intreacting cell death suppressor (BIS; also known as BAG3) is an anti-apoptotic protein that is highly expressed in human cancers with various origins, including glioblastoma. In the present study, to investigate the role of BIS in GSC subpopulation, we examined the expression profile of BIS in A172 and U87-MG glioblastoma cell lines under specific in vitro culture conditions that enrich GSC-like cells in spheres. Both BIS mRNA and protein levels significantly increased under the sphere-forming condition as compared with standard culture conditions. BIS depletion resulted in notable decreases in sphere-forming activity and was accompanied with decreases in SOX-2 expression. The expression of STAT3, a master regulator of stemness, also decreased following BIS depletion concomitant with decreases in the nuclear levels of active phosphorylated STAT3, while ectopic STAT3 overexpression resulted in recovery of sphere-forming activity in BIS-knockdown glioblastoma cells. Additionally, immunoprecipitation and confocal microscopy revealed that BIS physically interacts with STAT3. Furthermore, BIS depletion increased STAT3 ubiquitination, suggesting that BIS is necessary for STAT3 stabilization in GSC-like cells. BIS depletion also affected epithelial-to-mesenchymal transition-related genes as evidenced by decrease in SNAIL and MMP-2 expression and increase in E-cadherin expression in GSC-like cells. Our findings suggest that high levels of BIS expression might confer stem-cell-like properties on cancer cells through STAT3 stabilization, indicating that BIS is a potential target in cancer therapy.
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