Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
FEBS J. 2021 May;288(9):2888-2910. doi: 10.1111/febs.15636. Epub 2020 Dec 2.
Poly (ADP-ribose) polymerase 1 (PARP1) and polycomb-repressive complex 2 (PRC2) are each known for their individual roles in cancer, but their cooperative roles have only been studied in the DNA damage repair process in the context of BRCA-mutant cancers. Here, we show that simultaneous inhibition of PARP1 and PRC2 in the MDA-MB-231 BRCA-proficient triple-negative breast cancer (TNBC) cell line leads to a synthetic viability independent of the mechanisms of DNA damage repair. Specifically, we find that either genetic depletion or pharmacological inhibition of both PARP1 and PRC2 can accelerate tumor growth rate. We attribute this to modifications in the tumor microenvironment (TME) that are induced by double-depleted breast cancer cells, such as promoting intratumoral angiogenesis and increasing the proportion of tumor-promoting type 2 (M2) macrophages. These changes subsequently inhibit cell death and promote proliferation. Mechanistically, we find that PARP1 and PRC2 double depletion induces not only a basal activation of the NF-κB pathway but also a maximal activation of NF-κB within the TME in response to external stimuli such as hypoxia and the presence of macrophages. In summary, our study reveals an unprecedented synthetic viable interaction between PARP1 and PRC2 in BRCA-proficient TNBC and identifies NF-κB as the downstream mediator. DATABASE: RNA-seq data are available in the GEO databases under the accession GSE142769.
聚（ADP-核糖）聚合酶 1（PARP1）和多梳抑制复合物 2（PRC2）各自在癌症中具有其独特的作用，但它们在 BRCA 突变型癌症的 DNA 损伤修复过程中的协同作用仅在研究中被研究过。在这里，我们表明，在 MDA-MB-231 BRCA 功能齐全的三阴性乳腺癌（TNBC）细胞系中同时抑制 PARP1 和 PRC2 会导致与 DNA 损伤修复机制无关的合成生存能力。具体而言，我们发现，PARP1 和 PRC2 的遗传耗竭或药理学抑制都可以加速肿瘤生长速度。我们将其归因于双重耗尽的乳腺癌细胞诱导的肿瘤微环境（TME）的改变，例如促进肿瘤内血管生成和增加促进肿瘤的 2 型（M2）巨噬细胞的比例。这些变化随后抑制细胞死亡并促进增殖。从机制上讲，我们发现 PARP1 和 PRC2 的双重耗竭不仅诱导 NF-κB 途径的基础激活，而且在外部刺激（例如缺氧和巨噬细胞的存在）下，在 TME 中还可以最大程度地激活 NF-κB。总之，我们的研究揭示了 BRCA 功能齐全的 TNBC 中 PARP1 和 PRC2 之间前所未有的合成生存能力相互作用，并确定 NF-κB 为下游介质。数据库：RNA-seq 数据可在 GEO 数据库中以 GEO accession GSE142769 的形式获得。
