Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis.
Acetylation of androgen receptor by ARD1 promotes dissociation from HSP90 complex and prostate tumorigenesis.
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DOI：
10.18632/oncotarget.12163
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Liu W
中科院分区：
文献类型：
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作者：
DePaolo JS;Wang Z;Guo J;Zhang G;Qian C;Zhang H;Zabaleta J;Liu W
前列腺癌是一种雄激素受体（AR）驱动的疾病，AR的翻译后修饰对AR激活至关重要。我们以前报道过，Arrest-deficient蛋白1（ARD 1）是前列腺癌中的癌蛋白。它乙酰化并激活AR以促进前列腺肿瘤发生。然而，AR内的ARD 1靶向残基和前列腺肿瘤发生中的乙酰化事件的机制仍然未知。在这项研究中，我们表明，ARD 1乙酰化AR在赖氨酸618（K618）在体外和体内。由于AR核转位的减弱，具有精氨酸（AR-618 R）的带电赖氨酸取代的AR构建体减少RNA Pol II结合、AR转录活性、前列腺癌细胞生长和异种移植肿瘤形成，而模拟谷氨酰胺（AR-618 Q）在K618处的中性极性取代乙酰化的构建体增强了这些作用，超过了野生型AR的作用。从机制上讲，ARD 1在体外和体内与AR和HSP 90形成三元复合物。ARD 1的表达以剂量依赖性方式增加AR乙酰化和AR-HSP 90解离的水平。此外，AR乙酰化缺陷型K618 R突变体不能从HSP 90解离，而HSP 90解离的AR在配体暴露后被乙酰化。这项工作确定了配体诱导的AR-HSP 90解离和AR激活的新机制。靶向ARD 1介导的AR乙酰化可能是AR依赖性前列腺癌治疗的有效干预。
Prostate cancer is an androgen receptor (AR)-driven disease and post-translational modification of AR is critical for AR activation. We previously reported that Arrest-defective protein 1 (ARD1) is an oncoprotein in prostate cancer. It acetylates and activates AR to promote prostate tumorigenesis. However, the ARD1-targeted residue within AR and the mechanisms of the acetylation event in prostate tumorigenesis remained unknown. In this study, we show that ARD1 acetylates AR at lysine 618 (K618) in vitro and in vivo. An AR construct with the charged lysine substitution by arginine (AR-618R) reduces RNA Pol II binding, AR transcriptional activity, prostate cancer cell growth, and xenograft tumor formation due to attenuation of AR nuclear translocation, whereas, construct mimicking neutral polar substitution acetylation at K618 by glutamine (AR-618Q) enhanced these effects beyond that of the wild-type AR. Mechanistically, ARD1 forms a ternary complex with AR and HSP90 in vitro and in vivo. Expression of ARD1 increases levels of AR acetylation and AR-HSP90 dissociation in a dose dependent manner. Moreover, the AR acetylation defective K618R mutant is unable to dissociate from HSP90 while the HSP90-dissociated AR is acetylated following ligand exposure. This work identifies a new mechanism for ligand-induced AR-HSP90 dissociation and AR activation. Targeting ARD1-mediated AR acetylation may be a potent intervention for AR-dependent prostate cancer therapy.