Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation

Abstract

The transcriptional activity of the androgen receptor is regulated by both ligand binding and posttranslational modifications including acetylation and SUMOylation. Histone deacetylases are known to catalyze the removal of acetyl groups from both histones and non-histone proteins. In the present study, we report that histone deacetylase 4 (HDAC4) binds to and inhibits the activity of the androgen receptor (AR). This inhibition was found to depend on the SUMOylation, instead of deacetylation, of the AR. Consistently, HDAC4 increases the level of AR SUMOylation in both whole cell and cell-free assay systems, raising the possibility that the deacetylase may act as an E3 ligase for AR SUMOylation. Knock down of HDAC4 increases the activity of endogenous AR and androgen induction of prostate specific antigen expression and prostate cancer cell growth, which is associated with decreased SUMOylation of the receptor. Overall, the studies identify HDAC4 as a positive regulator for AR SUMOylation, revealing a deacetylase-independent mechanism of histone deacetylase action in prostate cancer cells.