CSIG-05. THE HISTONE CHAPERONE Spt6 IS REQUIRED FOR GENOMIC STABILITY OF GLIOBLASTOMA CANCER STEM-LIKE CELLS. Issue 11 (6th November 2017) - Rasmussen, Rikke
Abstract: Rampant genomic instability is a hallmark of glioblastoma (GBM). Despite recent advances in our understanding of this deadly disease, molecular mechanism contributing to treatment resistance are poorly understood. Histone chaperones regulate chromatin structure and gene expression through interaction with histones and RNA polymerase II. Spt6 is a highly conserved transcription elongation factor and histone chaperone. We have identified a novel role of Spt6 in glioblastoma-derived cancer stem-like cells (GSCs) using high-throughput siRNA microscopy-based screening. Our data show that the loss of Spt6 in GSCs, but not their differentiated counterparts (non-GSCs), results in decreased proliferation rates, cell cycle arrest and increased double-strand DNA breaks due to hyper-activation of error-prone non-homologous end-joining DNA repair (NHEJ). Importantly, shRNA-mediated knockdown significantly impairs tumor initiation capacity of GSCs and extends survival of tumor-bearing mice. Our findings indicate an important role of Spt6 in glioblastoma maintenance and resistance to DNA damaging therapies.