Targeting transcriptional factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C

In this study, we screened KDM5C-binding proteins and found that Yin Yang 1 (YY1) interacts with KDM5C. Interestingly, a synergistic antitumor effect was exerted when both KDM5C and YY1 were depleted, and targeting YY1 appeared to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C is essential for 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 revealed that dual inhibition of KDM5C and YY1 led to significantly increased transcriptional repression of many cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests a therapeutic vulnerability that can be targeted using combination therapies. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for YY1 and H3K4me3 in ACHN cells or HK2 cells.

本研究通过筛选KDM5C结合蛋白，发现阴阳1（Yin Yang 1, YY1）可与KDM5C发生相互作用。值得注意的是，当同时敲除KDM5C与YY1时，可产生协同抗肿瘤效应；且靶向YY1似乎是KDM5C缺陷型癌细胞的一个治疗脆弱位点。从机制层面来看，KDM5C对于YY1在全基因组范围内的染色质招募至关重要，尤其在启动子区域。此外，KDM5C介导的YY1染色质结合需要完整的KDM5C JmjC结构域，而非KDM5C的组蛋白去甲基化酶活性。转录组分析显示，同时抑制KDM5C与YY1可显著增强众多细胞周期与凋亡相关基因的转录抑制水平。综上，本研究证实了YY1与KDM5C之间存在合成致死相互作用，并提出了可通过联合疗法靶向的治疗脆弱位点。本数据集包含针对ACHN细胞或HK2细胞中YY1与H3K4me3的染色质免疫沉淀测序（Chromatin immunoprecipitation DNA-sequencing, ChIP-seq）数据。