Year: 2017
Type: conference-abstract
Abstract: Glioblastoma is highly resistant to chemo- and radiotherapy. Despite treatment, median survival is only 12-15 months. Tumor cells rely upon elevated stress response pathways to survive and maintain a rapid proliferative rate in the harsh tumor microenvironment. Glioblastoma stem cells (GSCs) are particularly enriched in their ability to survive in the context of nutrient deprivation, high reactive oxygen species, DNA damage and radiation. Upregulation of heat shock proteins (HSPs) and the unfolded proteins response (UPR) promote cell survival during stress. These pathways are elevated in glioblastoma and knockdown induces chemosensitivity and cell death. We performed an in silico analysis using The Cancer Genome Atlas database to identify genes that were upregulated in glioblastoma vs. normal brain, and genes for which higher expression was associated with worse survival. We intersected these gene sets to identify genes that may contribute to worse outcome in glioblastoma. In vitro validation of our tops hits revealed that RSAD1 (Radical S-Adenosyl Methionine Domain Containing 1) is critical for GSC survival and proliferation. We have further identified RSAD1 as a novel dependency in GSCs and a putative mediator of the UPR in glioblastoma stem cells. RSAD1 expression is increased in GSCs versus their differentiated counterparts and GSCs have a stem cell-specific transcriptional peak at the RSAD1 promoter as determined by histone 3 lysine 27 acetyl chromatin immunoprecipitation followed by deep sequencing (H3K27ac ChIP-seq). RSAD1 knockdown significantly impairs proliferation in GSCs in vitro. Preliminary evidence suggests that RSAD1 binding partners enrich for UPR regulators and HSPs. Future work will determine whether RSAD1 promotes survival in GSCs through activation of the UPR, and therefore represents a potential chemo- or radiosensitizer of GSCs with the potential to serve as a novel target for synergistic therapy in glioblastoma.
Source: Neuro-Oncology
Authors: Briana Prager, Qi Xie, Jeremy Rich
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767893737