Brain Tumor Biology, Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen DK-2100, Denmark.
Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Hnevotinska 3, Olomouc 77515, Czech Republic.
Nat Commun. 2016 Nov 15;7:13398. doi: 10.1038/ncomms13398.
Oncogene-evoked replication stress (RS) fuels genomic instability in diverse cancer types. Here we report that BRCA1, traditionally regarded a tumour suppressor, plays an unexpected tumour-promoting role in glioblastoma (GBM), safeguarding a protective response to supraphysiological RS levels. Higher BRCA1 positivity is associated with shorter survival of glioma patients and the abrogation of BRCA1 function in GBM enhances RS, DNA damage (DD) accumulation and impairs tumour growth. Mechanistically, we identify a novel role of BRCA1 as a transcriptional co-activator of RRM2 (catalytic subunit of ribonucleotide reductase), whereby BRCA1-mediated RRM2 expression protects GBM cells from endogenous RS, DD and apoptosis. Notably, we show that treatment with a RRM2 inhibitor triapine reproduces the BRCA1-depletion GBM-repressive phenotypes and sensitizes GBM cells to PARP inhibition. We propose that GBM cells are addicted to the RS-protective role of the BRCA1-RRM2 axis, targeting of which may represent a novel paradigm for therapeutic intervention in GBM.
癌基因诱发的复制应激（RS）为多种癌症类型的基因组不稳定性提供燃料。在这里，我们报告称，BRCA1 传统上被认为是一种肿瘤抑制因子，在胶质母细胞瘤（GBM）中发挥了出人意料的肿瘤促进作用，为应对超生理 RS 水平的保护反应提供了保障。BRCA1 阳性率较高与胶质瘤患者的生存时间较短相关，而在 GBM 中消除 BRCA1 功能会增强 RS、DNA 损伤（DD）积累并损害肿瘤生长。从机制上讲，我们确定了 BRCA1 作为核糖核苷酸还原酶（RR）催化亚基 RRM2 的转录共激活因子的新作用，BRCA1 介导的 RRM2 表达可保护 GBM 细胞免受内源性 RS、DD 和细胞凋亡的影响。值得注意的是，我们表明，用 RRM2 抑制剂三嗪处理可再现 BRCA1 耗尽的 GBM 抑制表型，并使 GBM 细胞对 PARP 抑制剂敏感。我们提出，GBM 细胞依赖于 BRCA1-RRM2 轴的 RS 保护作用，针对该轴的治疗干预可能代表 GBM 的一种新治疗模式。
