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

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.