Department of Oncology, Oxford Institute for Radiation Oncology, The University of Oxford, UK.
Laboratory of Molecular Neurobiology, Neurobiology Center, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Mol Oncol. 2023 Jul;17(7):1173-1191. doi: 10.1002/1878-0261.13431. Epub 2023 Apr 22.
Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those that are decreased in hypoxia. We demonstrate that chromatin accessibility is decreased in hypoxia, predominantly at gene promoters and specific pathways are impacted including DNA repair, splicing, and the R-loop interactome. One of the genes with decreased chromatin accessibility in hypoxia was DDX5, encoding the RNA helicase, DDX5, which showed reduced expression in various cancer cell lines in hypoxic conditions, tumor xenografts, and in patient samples with hypoxic tumors. Most interestingly, we found that when DDX5 is rescued in hypoxia, replication stress and R-loop levels accumulate further, demonstrating that hypoxia-mediated repression of DDX5 restricts R-loop accumulation. Together these data support the hypothesis that a critical part of the biological response to hypoxia is the repression of multiple R-loop processing factors; however, as shown for DDX5, their role is specific and distinct.
局部缺氧发生在大多数实体瘤中，并与侵袭性疾病和治疗抵抗有关。基因表达的广泛变化在对缺氧的生物学反应中起着关键作用。然而，大多数研究都集中在缺氧诱导基因上，而不是在缺氧时减少的基因上。我们证明，在缺氧条件下，染色质可及性降低，主要发生在基因启动子处，受影响的特定途径包括 DNA 修复、剪接和 R 环相互作用组。在缺氧时染色质可及性降低的基因之一是 DDX5，它编码 RNA 解旋酶 DDX5，在缺氧条件下各种癌细胞系、肿瘤异种移植和缺氧肿瘤患者样本中，DDX5 的表达降低。最有趣的是，我们发现当 DDX5 在缺氧时被挽救时，复制应激和 R 环水平进一步积累，表明缺氧介导的 DDX5 抑制限制了 R 环的积累。这些数据共同支持了这样一种假设，即对缺氧的生物学反应的一个关键部分是对多个 R 环处理因子的抑制；然而，如 DDX5 所示，它们的作用是特定和不同的。
