Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation.
Protein phosphatase 1 suppresses androgen receptor ubiquitylation and degradation.
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DOI：
10.18632/oncotarget.6434
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发表时间：
2016-01-12
期刊：
影响因子：
--
通讯作者：
Chen S
中科院分区：
文献类型：
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作者：
Liu X;Han W;Gulla S;Simon NI;Gao Y;Cai C;Yang H;Zhang X;Liu J;Balk SP;Chen S
磷蛋白磷酸酶正在成为前列腺癌 (PCa) 中重要的雄激素受体 (AR) 调节剂。我们之前报道过，蛋白磷酸酶1催化亚基（PP1α）可以通过使AR铰链区（Ser650）中的一个位点去磷酸化来增强AR活性，从而减少AR核输出。在这项研究中，我们表明 PP1α 增加了野生型以及 S650A 突变体 AR 的表达，表明它通过一种或多种其他机制发挥作用。接下来我们表明 PP1α 主要与 AR 配体结合域结合并减少其泛素化和降解。此外，我们发现 PP1α 抑制剂 tautomycin 会增加 AR 泛素连接酶（包括 SKP2 和 MDM2）在增强其活性的位点的磷酸化，从而提供了 PP1α 抑制 AR 降解的机制。值得注意的是，在低雄激素水平或存在 AR 拮抗剂恩杂鲁胺的情况下，互变霉素介导的 AR 表达降低最为明显。与这一发现一致，通过 PSA 合成和增殖评估，LNCaP 和 C4-2 PCa 细胞对互变霉素的敏感性在低雄激素水平或恩杂鲁胺治疗下增强。这些结果共同表明，PP1α 可能有助于雄激素剥夺治疗后 AR 蛋白的稳定，并且靶向 PP1α 或 AR-PP1α 相互作用可能对去势抵抗性前列腺癌 (CRPC) 有效。
The phosphoprotein phosphatases are emerging as important androgen receptor (AR) regulators in prostate cancer (PCa). We reported previously that the protein phosphatase 1 catalytic subunit (PP1α) can enhance AR activity by dephosphorylating a site in the AR hinge region (Ser650) and thereby decrease AR nuclear export. In this study we show that PP1α increases the expression of wildtype as well as an S650A mutant AR, indicating that it is acting through one or more additional mechanisms. We next show that PP1α binds primarily to the AR ligand binding domain and decreases its ubiquitylation and degradation. Moreover, we find that the PP1α inhibitor tautomycin increases phosphorylation of AR ubiquitin ligases including SKP2 and MDM2 at sites that enhance their activity, providing a mechanism by which PP1α may suppress AR degradation. Significantly, the tautomycin mediated decrease in AR expression was most pronounced at low androgen levels or in the presence of the AR antagonist enzalutamide. Consistent with this finding, the sensitivity of LNCaP and C4–2 PCa cells to tautomycin, as assessed by PSA synthesis and proliferation, was enhanced at low androgen levels or by treatment with enzalutamide. Together these results indicate that PP1α may contribute to stabilizing AR protein after androgen deprivation therapies, and that targeting PP1α or the AR-PP1α interaction may be effective in castration-resistant prostate cancer (CRPC).