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首页> 外文期刊>Oncogene >PIAS1 is a determinant of poor survival and acts as a positive feedback regulator of AR signaling through enhanced AR stabilization in prostate cancer
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PIAS1 is a determinant of poor survival and acts as a positive feedback regulator of AR signaling through enhanced AR stabilization in prostate cancer

机译：PIAS1是存活率低的决定因素，并通过增强前列腺癌的AR稳定性而充当AR信号的正反馈调节剂

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Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies.
机译：在过去的几年中，已经开发出了新药，如阿比特龙或恩杂鲁胺，它们靶向雄激素受体（AR）信号来改善雄激素剥夺疗法（ADT）。然而，由于在治疗过程中固有或获得的治疗抗性的出现，这些药物的应用受到限制。因此，迫切需要鉴定新的分子靶标以改善当前的治疗性前列腺癌（PCa）治疗策略。已知PIAS1（活化的STAT1（信号转导和转录激活因子1）的蛋白抑制剂）是重要的细胞周期调节剂，PIAS1介导的SUMOylation对DNA修复至关重要。在这种情况下，PIAS1表达的升高已经与癌症的发生有关。因此，在本研究中，我们解决了是否可以将PIAS1靶向用作与抗雄激素结合的改良PCa治疗的基础的问题。我们表明，PIAS1与PCa组织和细胞系中的AR表达显着相关，并证明高PIAS1水平可预测较短的无复发生存期。我们的患者数据得到了机械和功能性体外实验的补充，这些实验确定PIAS1为雄激素响应基因，并且是通过防止AR降解而成为AR信号传导的关键因素。此外，PIAS1敲低足以减少细胞增殖以及细胞活力。令人惊讶的是，在多种PCa细胞模型中，阿比特龙或Enzalutamide联合PIAS1耗竭治疗比单药治疗更为有效，使PIAS1成为有望用于改善未来PCa治疗的联合治疗方法的靶蛋白。

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