Evidence that HDAC7 acts as an epigenetic "reader" of AR acetylation through NCoR-HDAC3 dissociation

Area of Science:

• Epigenetics
• Molecular Biology
• Cancer Biology

Background:

• Histone deacetylases (HDACs) are epigenetic regulators implicated in cancer.
• Class IIa HDACs (HDAC4, -5, -7, -9) have low catalytic activity and are proposed to be "reader" proteins.
• The functional consequences of class IIa HDACs acting as readers remain unclear.

Purpose of the Study:

• To investigate the potential "reader" function of class IIa HDACs.
• To determine if acetyllysine binding by class IIa HDACs has downstream functional effects.
• To explore the role of class IIa HDACs in regulating transcriptional activation.

Main Methods:

• In vitro assays using acetyllysine-containing peptides.
• Co-immunoprecipitation to assess protein interactions.
• Site-directed mutagenesis of acetylation sites.
• Analysis of androgen receptor (AR) transcriptional activity.

Main Results:

• HDAC4, -5, and -7 dissociated from the NCoR corepressor complex upon binding to an acetyllysine peptide.
• Mutation of a key acetylation site in HDAC7 disrupted the HDAC7-NCoR-HDAC3 complex.
• This disruption altered androgen receptor transcriptional activation, demonstrating a functional consequence.

Conclusions:

• This study provides the first evidence supporting the epigenetic "reader" function of class IIa HDAC proteins.
• Class IIa HDACs' interaction with acetylated proteins influences transcriptional regulation.
• These findings offer new insights into HDAC function and potential therapeutic targets in epigenetic regulation.