title: BIS-mediated STAT3 stabilization regulates glioblastoma stem cell-like phenotypes.
abstract: 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.
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Chang-Nim
authors.initials: CN
authors.lastname: Im
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hye Hyeon
authors.initials: HH
authors.lastname: Yun
authors.affiliation: Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Byunghoo
authors.initials: B
authors.lastname: Song
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong-Ye
authors.initials: DY
authors.lastname: Youn
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Mei Nu
authors.initials: MN
authors.lastname: Cui
authors.affiliation: NGS Clinical Department, Macrogen Inc., Seoul, Korea.
authors.forename: Hong Sug
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Gyeong Sin
authors.initials: GS
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, Seoul, Korea.|Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Jeong-Hwa
authors.initials: JH
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: BIS; CSCs; STAT3; glioblastoma; ubiquitination