了解表观遗传修饰剂的酶和支架功能对于癌症表观遗传疗法的开发非常重要。 H3K4me2/3 组蛋白去甲基化酶 KDM5C 已被证明可以调节转录。 KDM5C 的多种作用很可能是由其相互作用的伙伴决定的，而这些伙伴在很大程度上仍然未知。在这项研究中，我们筛选了 KDM5C 结合蛋白并表明 YY1 与 KDM5C 相互作用。当 KDM5C 和 YY1 都被耗尽时，会发挥协同抗肿瘤作用，而靶向 YY1 似乎是 KDM5C 缺陷的癌细胞中的一个弱点。从机制上讲，KDM5C 促进全局 YY1 染色质招募，尤其是在启动子处。此外，KDM5C 介导的 YY1 染色质结合需要完整的 KDM5C JmjC 结构域，但不需要 KDM5C 组蛋白去甲基酶活性。转录分析表明，KDM5C 和 YY1 的双重抑制会增加细胞周期和凋亡相关基因的转录抑制。总之，我们的工作证明了 YY1 和 KDM5C 之间的合成致死相互作用，并建议癌症治疗的联合疗法。© 2024。作者。

An understanding of the enzymatic and scaffolding functions of epigenetic modifiers is important for the development of epigenetic therapies for cancer. The H3K4me2/3 histone demethylase KDM5C has been shown to regulate transcription. The diverse roles of KDM5C are likely determined by its interacting partners, which are still largely unknown. In this study, we screen for KDM5C-binding proteins and show that YY1 interacts with KDM5C. A synergistic antitumor effect is exerted when both KDM5C and YY1 are depleted, and targeting YY1 appears to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C promotes global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding. Transcriptional profiling reveals that dual inhibition of KDM5C and YY1 increases transcriptional repression of cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests combination therapies for cancer treatments.© 2024. The Author(s).