Abstract
Heat shock factor 1 (HSF1), a transcription factor activated by various stressors, regulates proliferation and apoptosis by inducing expression of target genes, such as heat shock proteins and Bcl-2 (B-cell lymphoma 2) interacting cell death suppressor (BIS). HSF1 also directly interacts with BIS, although it is still unclear whether this interaction is critical in the regulation of glioblastoma stem cells (GSCs). In this study, we examined whether small interfering RNA-mediated BIS knockdown decreased protein levels of HSF1 and subsequent nuclear localization under GSC-like sphere (SP)-forming conditions. Consistent with BIS depletion, HSF1 knockdown also reduced sex determining region Y (SRY)-box 2 (SOX2) expression, a marker of stemness, accompanying the decrease in SP-forming ability and matrix metalloprotease 2 (MMP2) activity. When HSF1 or BIS knockdown was combined with temozolomide (TMZ) treatment, a standard drug used in glioblastoma therapy, apoptosis increased, as measured by an increase in poly (ADP-ribose) polymerase (PARP) cleavage, whereas cancer stem-like properties, such as colony-forming activity and SOX2 protein expression, decreased. Taken together, our findings suggest that targeting BIS or HSF1 could be a viable therapeutic strategy for GSCs resistant to conventional TMZ treatment.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive of brain tumors
Heat shock factor 1 (HSF1) is considered a potential target for anti-cancer therapy because it is overexpressed in several cancers, including breast cancer, and increased expression has been associated with poor prognosis [3,4]
A172 glioblastoma cells were transfected with 100 nM BIS small interfering RNA for 48 h and cultured under SP-forming conditions, which we established in a previous study [15]
Summary
Glioblastoma multiforme (GBM) is the most aggressive of brain tumors. Glioblastoma stem cells (GSCs) are a subpopulation of tumor cells that develop resistance to the DNA alkylating agent temozolomide (TMZ), the conventional drug used in GBM therapy following surgery, resulting in tumor recurrence [1]. Transcription of BIS is regulated by HSF1 through two main heat shock elements (HSEs) in the BIS promoter region in response to a variety of stimuli, including hydrogen peroxide and the proteasome inhibitor MG132, indicating that the transcription factor plays an important role in BIS gene expression [8,9,10]. BIS depletion inhibited GSC-like properties and SOX2 expression in glioblastoma cell lines under the same conditions [16]. We hypothesized that BIS plays a key role in stemness-related properties via HSF1 regulation and that BIS or HSF1 depletion combined with TMZ treatment would induce apoptosis in SPs of the glioblastoma cell line A172
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