Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation.
Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation.
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DOI：
10.1038/onc.2010.600
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发表时间：
2011-05-12
期刊：
影响因子：
8
通讯作者：
Bai, W.
中科院分区：
文献类型：
--
作者：
Yang, Y.;Tse, A. K-W;Li, P.;Ma, Q.;Xiang, S.;Nicosia, S. V.;Seto, E.;Zhang, X.;Bai, W.
雄激素受体的转录活性受配体结合和翻译后修饰（包括乙酰化和SUMOylation）的调节。已知组蛋白去乙酰化酶可以催化从组蛋白和非组蛋白中去除乙酰基。在本研究中，我们报道了组蛋白去乙酰化酶4 （HDAC4）结合并抑制雄激素受体（AR）的活性。这种抑制作用依赖于AR的summoylation，而不是去乙酰化。一致地，HDAC4增加了全细胞和无细胞检测系统中AR summoylation的水平，这提高了去乙酰化酶可能作为AR summoylation的E3连接酶的可能性。敲低HDAC4可增加内源性AR活性和雄激素诱导前列腺特异性抗原表达和前列腺癌细胞生长，这与该受体SUMOylation降低有关。总体而言，这些研究确定HDAC4是AR sumo化的正调节因子，揭示了前列腺癌细胞中组蛋白去乙酰化酶作用的非去乙酰化酶独立机制。
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.
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