Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen, DK-2100, Denmark.
Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen, DK-2200, Denmark.
Nat Commun. 2020 Sep 18;11(1):4709. doi: 10.1038/s41467-020-18549-8.
Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.
胶质母细胞瘤癌干细胞（GSCs）对电离辐射（IR）表现出明显的抗性，IR 是胶质母细胞瘤患者的标准治疗方法。GSCs 辐射抗性的机制在很大程度上尚不清楚。染色质状态和 DNA 损伤对 DNA 修复机制的可及性对于维持基因组稳定性至关重要。了解染色质重塑对 GSCs 中 DNA 修复的功能影响可能为提高放射增敏治疗的疗效奠定基础。在这里，我们展示了高内涵 siRNA 显微镜筛选的结果，结果表明转录延伸因子 SPT6 对于 GSCs 的基因组稳定性和自我更新至关重要。从机制上讲，SPT6 转录上调 BRCA1，从而驱动 GSCs 中无错误的 DNA 修复。SPT6 的缺失会损害 GSCs 的自我更新、基因组稳定性和肿瘤起始能力。总的来说，我们的结果提供了 SPT6 如何调节 DNA 修复的机制见解，并确定 SPT6 是胶质母细胞瘤的一个潜在治疗靶点。
