Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition

Area of Science:

• Epigenetics
• Transcriptomics
• Cancer Biology

Background:

• Histone acetylation regulates gene expression and chromatin structure.
• Lysine acetyltransferases like P300 and CBP are crucial for maintaining acetylation homeostasis.
• Dysregulation of acetylation is implicated in hematological malignancies.

Purpose of the Study:

• To elucidate the distinct roles of histone acetylation in chromatin accessibility versus transcriptional output.
• To identify key regulators of acetylation turnover in cancer cells.
• To explore therapeutic strategies targeting the acetylation-methylation balance.

Main Methods:

• Integrated epigenomic and transcriptomic analyses in hematological malignancy models.
• Acute inhibition of P300 and CBP acetyltransferases.
• CRISPR-Cas9 screening to identify antagonistic co-repressors.
• Analysis of histone modifications, including acetylation and methylation.

Main Results:

• Catalytic inhibition of P300/CBP dynamically perturbs acetylation kinetics and suppresses oncogenic transcription.
• Chromatin accessibility remained unchanged upon P300/CBP inhibition.
• NCOR1 and HDAC3 were identified as key antagonists of P300/CBP activity.
• H3K27 deacetylation facilitates methylation switching, offering a therapeutic target.

Conclusions:

• Steady-state histone acetylation acts as a molecular rheostat controlling cellular transcription.
• Targeting acetylation turnover, rather than accessibility, is key for anti-cancer effects.
• Concomitant inhibition of KDM6A and P300/CBP presents a potential therapeutic strategy.