Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
Nat Commun. 2024 Oct 29;15(1):9321. doi: 10.1038/s41467-024-53515-8.
Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
SMARCB1 中的失活突变赋予了非典型畸胎样横纹肌样肿瘤（ATRT）对 EZH2 的致癌依赖性，但潜在的机制尚未完全阐明。我们发现，ATRT 对 EZH2 抑制剂（EZH2i）的敏感性与病毒模拟反应有关。与其他针对转录抑制剂的表观遗传治疗不同，EZH2i 诱导的病毒模拟不是由内源性逆转录元件的隐匿转录触发的，而是由富含内含子反转录 Alu（IR-Alu）元件的基因表达增加介导的。有趣的是，干扰素刺激基因（ISGs）富含形成 dsRNA 的内含子 IR-Alu 元件，这表明存在正反馈回路，其中这些激活的 ISGs 可能增强 dsRNA 的形成和病毒模拟。EZH2i 还上调全长 LINE-1 的表达，导致基因组不稳定性和 cGAS/STING 信号传导，这一过程依赖于逆转录酶活性。dsRNA 感应和细胞质 DNA 感应的共同耗竭完全挽救了 SMARCB1 缺陷肿瘤对 EZH2i 的病毒模拟反应。
