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

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Epigenetic modifiers are key targets for cancer therapy.
• KDM5C (lysine demethylase 5C) is an epigenetic modifier regulating transcription.
• KDM5C's interacting partners and full functional roles remain largely uncharacterized.

Purpose of the Study:

• To identify KDM5C-binding proteins.
• To elucidate the functional relationship between KDM5C and its interacting partners in cancer.
• To explore therapeutic strategies based on KDM5C-YY1 interactions.

Main Methods:

• Protein-protein interaction screening to identify KDM5C interactors.
• Depletion studies (siRNA/shRNA) of KDM5C and YY1.
• Chromatin immunoprecipitation (ChIP) assays to assess protein recruitment.
• Transcriptional profiling (RNA-seq) to analyze gene expression changes.

Main Results:

• YY1 was identified as a KDM5C-interacting protein.
• Co-depletion of KDM5C and YY1 demonstrated a synergistic antitumor effect.
• KDM5C facilitates global YY1 chromatin recruitment, particularly at gene promoters, via its JmjC domain.
• Targeting YY1 is a vulnerability in KDM5C-deficient cancer cells.
• Dual inhibition of KDM5C and YY1 repressed cell cycle and apoptosis genes.

Conclusions:

• A functional and synthetic lethal interaction exists between KDM5C and YY1.
• KDM5C's JmjC domain, not its demethylase activity, is critical for YY1 chromatin binding.
• Combined targeting of KDM5C and YY1 offers a potential therapeutic strategy for cancer treatment.