Institute for Translational Epigenetics, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Cell Death Dis. 2021 May 24;12(6):530. doi: 10.1038/s41419-021-03810-9.
Non-coding RNA from pericentromeric satellite repeats are involved in stress-dependent splicing processes, maintenance of heterochromatin, and are required to protect genome stability. Here we show that the long non-coding satellite III RNA (SatIII) generates resistance against the topoisomerase IIa (TOP2A) inhibitor etoposide in lung cancer. Because heat shock conditions (HS) protect cells against the toxicity of etoposide, and SatIII is significantly induced under HS, we hypothesized that the protective effect could be traced back to SatIII. Using genome methylation profiles of patient-derived xenograft mouse models we show that the epigenetic modification of the SatIII DNA locus and the resulting SatIII expression predict chemotherapy resistance. In response to stress, SatIII recruits TOP2A to nuclear stress bodies, which protects TOP2A from a complex formation with etoposide and results in decreased DNA damage after treatment. We show that BRD4 inhibitors reduce the expression of SatIII, restoring etoposide sensitivity.
着丝粒卫星重复非编码 RNA 参与应激依赖的剪接过程、异染色质的维持，并需要保护基因组稳定性。在这里，我们表明长非编码卫星 III RNA (SatIII) 可赋予肺癌细胞对拓扑异构酶 IIa (TOP2A) 抑制剂依托泊苷的抗性。由于热休克条件 (HS) 可保护细胞免受依托泊苷的毒性，并且 SatIII 在 HS 下显著诱导，我们假设这种保护作用可以追溯到 SatIII。使用源自患者的异种移植小鼠模型的基因组甲基化图谱，我们表明 SatIII DNA 基因座的表观遗传修饰和由此产生的 SatIII 表达可预测化疗耐药性。在应激反应中，SatIII 将 TOP2A 招募到核应激体中，从而保护 TOP2A 免受与依托泊苷的复合物形成，并导致治疗后 DNA 损伤减少。我们表明 BRD4 抑制剂可降低 SatIII 的表达，恢复依托泊苷的敏感性。
