DNMT3A 是一种重要的表观遗传调控酶。然而，由于其异质性和在各种癌症中频繁突变，DNMT3A 的作用仍然存在争议。在这里，我们确定了 DNMT3A 在非小细胞肺癌 (NSCLC) 中的作用，以确定潜在的治疗策略。为了研究 DNMT3A 功能丧失突变在 NSCLC 中的作用，使用 CRISPR/Cas9 诱导 DNMT3A 失活突变。筛选表观遗传抑制剂库以找到 DNMT3A 的合成致死伴侣。使用药理学抑制剂和基因操作来评估 DNMT3A/KDM1A 的体外和体内合成致死功效。最后，应用MS-PCR、ChIP-qPCR、双荧光素酶报告基因检测和临床样本分析来阐明合成致死相互作用的调节机制。我们确定DNMT3A是NSCLC中的抑癌基因，而KDM1A是DNMT3A的合成致死伙伴。删除。化学 KDM1A 抑制剂和基因操作都可以通过体外和体内诱导细胞凋亡来选择性降低 DNMT3A-KO 细胞的活力。我们阐明，综合致死不仅限于死亡模式，还涉及肿瘤转移。从机制上讲，DNMT3A 缺陷通过降低 KDM1A 启动子的甲基化状态诱导 KDM1A 上调，临床样本分析表明 DNMT3A 表达与 KDM1A 水平呈负相关。我们的结果为 DNMT3A 在 NSCLC 中的作用提供了新的见解，并阐明了合成的机制。 KDM1A 和 DNMT3A 之间的致命相互作用，这可能代表了治疗 DNMT3A 缺陷肿瘤患者的一种有前途的方法。© 2024。作者，获得 Springer Nature Limited 的独家许可。

DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies.To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction.We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level.Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.