Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, 10065, USA.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
Nat Commun. 2021 Nov 18;12(1):6662. doi: 10.1038/s41467-021-27024-x.
SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3, suggesting a distinctive mode of Cul3 inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1 PCa are more susceptible to AR-targeted therapy.
SPOP 是一种 E3 泛素连接酶，作为一种前列腺特异性肿瘤抑制因子，通过几种关键底物介导致癌功能。然而，SPOP 调节的机制在很大程度上是未知的。在这里，我们已经确定了 G3BP1 是 SPOP 的一个相互作用蛋白，并作为 Cul3 的竞争性抑制剂起作用，这表明在前列腺癌（PCa）中 Cul3 的失活具有独特的模式。转录组分析和功能研究揭示了 G3BP1-SPOP 泛素信号轴，通过激活 AR 信号促进 PCa 的进展。此外，AR 直接上调 G3BP1 的转录，以进一步以正反馈的方式放大 G3BP1-SPOP 信号。我们的研究支持 G3BP1 在使肿瘤抑制性 Cul3 失活方面的基本作用，从而定义了一个不依赖于 SPOP 突变的 PCa 亚群。因此，存在比以前认为的更多的 SPOP 泛素连接酶缺陷型 PCa，并且这些 G3BP1 PCa 对 AR 靶向治疗更敏感。
