Potentiation of androgen receptor transcriptional activity by inhibition of histone deacetylation - rescue of transcriptionally compromised mutants
Potentiation of androgen receptor transcriptional activity by inhibition of histone deacetylation - rescue of transcriptionally compromised mutants
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DOI：
10.1677/joe.0.1820377
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发表时间：
2004-09-01
影响因子：
4
通讯作者：
Saatcioglu, F
中科院分区：
文献类型：
--
作者：
Korkmaz, CG;Fronsdal, K;Saatcioglu, F
雄激素对男性生殖系统的发育和维持至关重要，对前列腺癌的进展也很重要。雄激素的作用是由雄激素受体(AR)介导的，AR是核受体超家族中的一种配体调节的转录因子。我们和其他人以前已经证明CPEB结合蛋白(CBP)可以作为AR的共激活因子。与其他一些核受体共激活因子和/或与其相互作用的蛋白质一样，CBP具有组蛋白乙酰转移酶(HAT)活性，被认为有助于核受体的转录激活。因此，我们通过使用组蛋白去乙酰化酶(HDAC)抑制剂(HDACI)、曲古菌素A(TSA)、丁酸钠(Na-BUT)和脱脂肽(FR901228)来评估细胞中组蛋白乙酰化状态的增加是否会影响AR的转录活性。我们发现，抑制HDAC活性显著增加了LNCaP细胞内源性AR或HeLa细胞异位表达AR激活AR依赖报告结构转录的能力。此外，HDACIs增加了LNCaP细胞中雄激素依赖的前列腺特异性抗原(PSA)基因的激活，这一增加并不是由于核AR蛋白水平的增加。此外，抑制CBP HAT活性的病毒癌蛋白E1a完全抑制了HDACIs刺激AR介导的转录的能力，表明CBP参与了这一过程。AR的缺失突变表明，虽然C-末端的AF-2结构域是可有可无的，但N-末端的AF-1结构域是HDACIs增强AR作用所必需的，这与CBP激活AR N-末端缺失突变体的能力降低是一致的。此外，HDACi处理挽救了AF-2突变体反式激活潜能的不足。综上所述，我们的研究结果表明，靶基因组蛋白乙酰化水平的变化是AR作用的一个重要决定因素，可能是由CBP介导的。
Androgens are critical in the development and maintenance of the male reproductive system and important in the progression of prostate cancer. The effects of androgens are mediated by the androgen receptor (AR), which is a ligand-modulated transcription factor that belongs to the nuclear receptor superfamily. We and others have previously shown that CPEB-binding protein (CBP) can function as a coactivator for AR. Similar to some other nuclear receptor coactivators and/or the proteins that they interact with, CBP has histone acetyl transferase (HAT) activity that is thought to contribute to transcriptional activation by nuclear receptors. We have therefore assessed whether an increase in the histone acetylation status in the cell can influence AR transcriptional activity, by using the histone deacetylase (HDAC) inhibitors (HDACIs) trichostatin A (TSA), sodium butyrate (Na-But) and depsipeptide (FR901228). We found that inhibition of HDAC activity significantly increased the ability of endogenous AR in LNCaP cells, or ectopically expressed AR in HeLa cells, to activate transcription from AR-dependent reporter constructs. In addition, HDACIs increased the androgen-dependent activation of the prostate-specific antigen (PSA) gene in LNCaP cells, an increase that was not due to an increase in nuclear AR protein levels. Moreover, the viral oncoprotein E1A that inhibits CBP HAT activity fully repressed the ability of HDACIs to stimulate AR-mediated transcription, indicating that CBP is involved in this process. Deletional mutagenesis of AR indicated that whereas the AF-2 domain in the C-terminus is dispensable, the AF-1 domain in the N-terminus is required for augmentation of AR action by HDACIs, an observation which is in concordance with the reduced ability of CBP to activate AR N-terminal deletion mutants. Furthermore, HDACI treatment rescued the deficiency in the transactivation potential of AF-2 mutants. Taken together, our findings suggest that a change in the level of histone acetylation of target genes is an important determinant of AR action, possibly mediated by CBP.