Functional interplay between histone demethylase and deacetylase enzymes

Area of Science:

• Epigenetics
• Cancer Biology
• Molecular Oncology

Background:

• Histone deacetylase (HDAC) inhibitors are investigated as anticancer agents.
• HDAC inhibitors' precise anticancer mechanisms are under active research.
• Previously identified multiprotein complexes contain HDAC1/2 and the histone demethylase BHC110 (LSD1).

Purpose of the Study:

• To investigate the functional relationship between HDACs and BHC110.
• To determine if HDAC inhibitors affect BHC110 activity.
• To identify novel targets of HDAC inhibitors.

Main Methods:

• In vitro enzymatic assays using recombinant complexes.
• In vivo studies analyzing histone methylation and acetylation.
• Expression of enzymatically dead BHC110 mutant (K661A).

Main Results:

• HDAC inhibitors reduced BHC110-mediated histone H3 lysine 4 (H3K4) demethylation in vitro.
• In vivo, HDAC inhibitors increased H3K4 methylation alongside nucleosomal deacetylation inhibition.
• Functional crosstalk between HDAC1 and BHC110 was observed with nucleosomal substrates.
• Enzymatic activity of BHC110 is crucial for optimal in vitro deacetylation, but functional crosstalk occurs in vivo.

Conclusions:

• A close functional link exists between histone demethylase (BHC110) and deacetylase (HDAC) enzymes.
• Histone demethylation is identified as a secondary target of HDAC inhibitors.
• These findings offer new insights into the anticancer mechanisms of HDAC inhibitors.