Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer.
Histone deacetylases are required for androgen receptor function in hormone-sensitive and castrate-resistant prostate cancer.
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DOI：
10.1158/0008-5472.can-08-2216
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Sawyers CL
中科院分区：
文献类型：
--
作者：
Welsbie DS;Xu J;Chen Y;Borsu L;Scher HI;Rosen N;Sawyers CL
雄激素受体（AR）的转录活性对前列腺癌的生长和生存至关重要，即使在雄激素消融和抗雄激素治疗产生耐药性的情况下也是如此。因此，当传统激素治疗失败时，需要能够抑制AR转录活性的新疗法。在这里，我们表明组蛋白去乙酰化酶（HDAC）抑制剂，包括SAHA（伏立诺他）和LBH589，目前正在临床测试中，可能是这样的治疗方法。HDAC抑制剂阻断ar介导的许多基因的转录激活，包括在大多数前列腺癌中与ETS家族成员融合的TMPRSS2基因。基因敲低HDAC1或HDAC3也可以抑制ar调控基因的表达，概括了HDAC抑制剂治疗的效果。虽然HDAC抑制剂治疗可以降低前列腺癌细胞中的雄激素受体蛋白水平，但我们发现，在AR与靶基因的增强子结合后，HDAC抑制剂通过抑制辅助激活因子/RNA聚合酶II复合物的组装来阻断AR活性，而不依赖于AR蛋白水平。复合物组装失败与AR招募周期波中的相移有关，这种相移通常发生在对配体处理的响应中。在去势抵抗性前列腺癌模型中，HDAC抑制剂保留了阻断AR活性的能力，因此值得在这种情况下进行临床研究。这里定义的HDAC调控的AR靶基因可以作为生物标志物，以确保足够水平的HDAC抑制。
Transcriptional activity of the androgen receptor (AR) is crucial for growth and survival of prostate cancer even upon development of resistance to androgen ablation and antiandrogen therapies. Therefore, novel therapies that can suppress AR transcriptional activity when conventional hormone therapies fail are needed. Here, we show that histone deacetylase (HDAC) inhibitors, including SAHA (vorinostat) and LBH589, which are currently being tested in clinic, could be such a therapy. HDAC inhibitors block the AR-mediated transcriptional activation of many genes, including the TMPRSS2 gene involved in fusion with ETS family members in a majority of prostate cancers. Genetic knockdown of either HDAC1 or HDAC3 can also suppress expression of AR-regulated genes, recapitulating the effect of HDAC inhibitor treatment. Whereas HDAC inhibitor treatment can lower androgen receptor protein levels in prostate cancer cells, we show that independent of AR protein levels, HDAC inhibitors block AR activity through inhibiting the assembly of coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in castration-resistant prostate cancer models and, therefore, merit clinical investigation in this setting. The HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition.