PO.ET03.01 · 实验与分子治疗
非整倍体相关的RAD21扩增对尤因肉瘤和前列腺癌中PARP抑制治疗反应的影响
Effects of aneuploidy associated RAD21 gain on therapeutic response to PARP inhibition in Ewing sarcoma and prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
8号染色体（chr8）扩增，特别是其长臂8q的扩增，是多种人类癌症中最常见的染色体异常之一。在尤因肉瘤中，约50%的病例表现出chr8扩增，而在前列腺癌中，8q高水平扩增发生于约24%的原发病例，在转移病例中频率则高得多。在这两种疾病中，位于8q24.11区域的黏连蛋白亚基基因RAD21已成为一个关键驱动因素，它通过缓解与致癌基因激活相关的复制应激来促进chr8扩增。RAD21是一种高度保守的蛋白，对于建立姐妹染色单体黏连、染色质环化、DNA复制、转录调控和DNA损伤修复至关重要。我们近期的研究表明，RAD21表达升高与前列腺癌癌症特异性死亡率增加相关，凸显了其在肿瘤进展中的潜在作用。然而，RAD21如何缓解与复制应激相关的DNA损伤并调节治疗反应仍知之甚少。为填补这一空白，我们利用尤因肉瘤和前列腺癌细胞模型研究了RAD21在DNA损伤反应（DDR）和治疗耐药中的作用。使用基于TurboID的蛋白邻近标记和质谱，我们证明RAD21在致癌诱导时与包括PARP1和MRE11在内的多个关键DNA损伤起始因子相互作用，提示RAD21参与了DNA修复起始及同源重组（HR）相关的机制。鉴于DNA损伤诱导性PARP抑制剂（PARPi）在靶向HR缺陷型癌症中的临床应用，我们在经工程改造以表达不同水平RAD21的同基因尤因肉瘤和前列腺癌细胞模型中评估了FDA批准的PARPi。我们的数据显示，RAD21过表达在两种模型中均显著改变了细胞对PARP抑制的反应，且这一效应似乎独立于细胞周期调控，与RAD21增强HR介导的DNA修复的潜在作用相一致。总之，我们的发现揭示了RAD21在改变DNA修复和影响针对DNA修复通路的治疗药物反应中一个常被忽视的功能。黏连蛋白的失调可能促成治疗耐药，并可能作为对患者进行DDR靶向治疗分层的潜在生物标志物。
查看英文原文 English abstract
Chromosome 8 (chr8) gain, particularly the gain of its long arm 8q, represents one of the most frequent chromosomal abnormalities across multiple human cancers. In Ewing sarcoma, approximately 50% of cases exhibit chr8 gain while in prostate cancer, high level amplification of 8q occurs in about 24% of primary cases with much higher frequencies in metastatic cases. Across both diseases, the cohesin subunit gene RAD21 , located on 8q24.11 region, has emerged as a key driver that facilitates chr8 gain by alleviating replication stress associated with oncogene activation. RAD21 is a highly conserved protein essential for establishing sister chromatid cohesin, chromatin looping, DNA replication, transcriptional regulation, and DNA damage repair. Our recent study demonstrated that elevated RAD21 expression correlates with increased cancer-specific mortality in prostate cancer, underscoring its potential role in tumor progression. However, how RAD21 mitigates replication-stress-associated DNA damage and modulates therapeutic response remains poorly understood. To address this gap, we investigated RAD21's role in the DNA damage response (DDR) and treatment resistance using Ewing sarcoma and prostate cancer cell models. Using TurboID-based protein proximity labeling and mass spectrometry, we have demonstrated that RAD21 interacts with several key DNA damage initiating factors upon oncogenic induction including PARP1 and MRE11, suggesting that RAD21 engages with DNA repair initiating and homologous recombination (HR)-associated machinery. Given the clinical use of DNA damage-inducing PARP inhibitors (PARPi) for targeting HR-deficient cancers, we evaluated FDA-approved PARPi in isogenic Ewing sarcoma and prostate cancer cell models engineered to express distinct levels of RAD21. Our data showed that RAD21 overexpression markedly altered the cellular response to PARP inhibition in both models and this effect appears to be independent from cell-cycle regulation, consistent with a potential role for RAD21 enhancing HR-mediated DNA repair. In summary, our findings reveal an often overlooked function of RAD21 in altering DNA repair and influencing the response to therapeutic drugs targeting DNA repair pathways. Dysregulation of cohesin could contribute to therapeutic resistance and a potential biomarker for stratifying patients for DDR-targeted treatments.
利益披露 Disclosure
C. Springer, None..
E. DeArment, None..
R. W. Wang, None..
T. Janas, None..
X. A. Su, None.