Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function
Genistein down-regulates androgen receptor by modulating HDAC6-Hsp90 chaperone function
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DOI：
10.1158/1535-7163.mct-08-0617
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发表时间：
2008-10-01
影响因子：
5.7
通讯作者：
Dahiya, Rajvir
中科院分区：
文献类型：
--
作者：
Basak, Shashwati;Pookot, Deepa;Dahiya, Rajvir
雄激素受体（Androgen receptor，AR）是类固醇激素受体家族的一种配体激活的转录因子，在前列腺癌的发生、发展中起着重要作用。大豆异黄酮先前已显示下调雄激素依赖性前列腺癌细胞系如LNCaP中的AR。然而，染料木黄酮下调AR的机制仍不完全清楚。我们展示了染料木黄酮抑制AR蛋白水平的新机制。我们发现，染料木素处理的LNCaP细胞表现出增加的AR泛素化，这表明AR蛋白通过蛋白酶体介导的途径下调。AR通常由热休克蛋白Hsp 90的伴侣活性稳定。染料木素处理后AR的泛素化增加归因于Hsp 90分子伴侣活性降低，如通过其功能失活的乙酰化形式增加所评估的。与此结果一致，我们发现HDAC 6，这是一个热休克蛋白90脱乙酰酶，抑制染料木素的抗雌激素活性。因此，在这项研究中，我们阐明了一种新的机制，通过抑制HDAC 6-Hsp 90辅伴侣蛋白功能所需的稳定AR蛋白的染料木素下调AR。我们的研究结果表明，染料木黄酮可以作为一个潜在的化学预防剂前列腺癌沿着已知的HDAC 6和HSP 90的抑制剂。[Mol Cancer Ther 2008;7（10）：3195-202]
Androgen receptor (AR) is a ligand-activated transcription factor belonging to the steroid hormone receptor family and is very important for the development and progression of prostate cancer. The soy isoflavone genistein has been shown previously to down-regulate AR in androgen-dependent prostate cancer cell lines such as LNCaP. However, the mechanism(s) by which AR is down-regulated by genistein is still not known fully. We show a new mechanism by which genistein inhibits AR protein levels. We show that genistein-treated LNCaP cells exhibit increased ubiquitination of AR, suggesting that AR protein is down-regulated via a proteasome-mediated pathway. AR is normally stabilized by the chaperone activity of the heat shock protein Hsp90. The increased ubiquitination of AR after genistein treatment is attributed to decreased Hsp90 chaperone activity as assessed by its increased functionally inactive acetylated form. Consistent with this result, we find that HDAC6, which is a Hsp90 deacetylase, is inhibited by the antiestrogenic activity of genistein. Hence, in this study, we elucidate a novel mechanism of AR down-regulation by genistein through inhibition of HDAC6-Hsp90 cochaperone function required to stabilize AR protein. Our results suggest that genistein could be used as a potential chemopreventive agent for prostate cancers along with known inhibitors of HDAC6 and Hsp90. [Mol Cancer Ther 2008;7(10):3195-202]