Abstract
Histone deacetylase (HDAC) proteins are epigenetic regulators that govern a wide variety of cellular events. With a role in cancer formation, HDAC inhibitors have emerged as anti-cancer therapeutics. Among the eleven metal-dependent class I, II, and IV HDAC proteins targeted by inhibitor drugs, class IIa HDAC4, -5, -7, and -9 harbor low deacetylase activity and are hypothesized to be "reader" proteins, which bind to post-translationally acetylated lysine. However, evidence linking acetyllysine binding to a downstream functional event is lacking. Here, we report for the first time that HDAC4, -5, and -7 dissociated from corepressor NCoR in the presence of an acetyllysine-containing peptide, consistent with reader function. Documenting the biological consequences of this possible reader function, mutation of a critical acetylation site regulated androgen receptor (AR) transcriptional activation function through HDAC7-NCoR-HDAC3 dissociation. The data document the first evidence consistent with epigenetic-reader functions of class IIa HDAC proteins.
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