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.