A SIX1 degradation inducer blocks excessive proliferation of prostate cancer.
A SIX1 degradation inducer blocks excessive proliferation of prostate cancer.
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DOI：
10.7150/ijbs.67873
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发表时间：
2022
影响因子：
9.2
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Liao Y;Sun W;Shao Z;Liu Y;Zhong X;Deng Y;Liu F;Huang H;Liu J
前列腺癌（PC）由于其高发病率和雄激素剥夺治疗患者去势抵抗的发展，仍然是一个巨大的医学挑战。去泛素化酶是一类特异性水解底物上泛素链的酶，近年来被认为是肿瘤治疗的重要靶点。我们的前期研究表明，泛素特异性肽酶1（USP 1）作为一种去泛素化酶，与PC的增殖和去势抵抗有关。USP 1对SIX 1的稳定作用部分取决于葡萄糖调节蛋白75（GRP 75）的状态。在这项研究中，我们的目的是通过抑制USP 1-SIX 1轴来鉴定SIX 1降解诱导剂。我们筛选了一系列激酶抑制剂，并显示SNS-032是触发SIX 1泛素化降解的最佳候选物。SNS-032不仅抑制了USP 1-SIX 1轴的活性和细胞周期进程，而且导致PC细胞凋亡。此外，SNS-032和恩杂鲁胺的组合在AR-V7高表达的22 Rv 1细胞中协同诱导细胞凋亡并下调USP 1、SIX 1和AR/AR-V7的表达。总的来说，我们的研究结果可能会开发一种新的和有效的策略，以克服去势抵抗PC的识别SIX 1降解诱导剂通过靶向USP 1-SIX 1轴。
Prostate cancer (PC) remains a great medical challenge due to its high incidence and the development of castration resistance in patients treated with androgen deprivation therapy. Deubiquitinases, the enzymes that specifically hydrolyze ubiquitin chains on their substrates, were recently proposed as a serious of critical therapeutic targets for cancer treatment. Our previous study has been reported that the ubiquitin specific peptidase 1 (USP1) functionally acts as a deubiquitinase of sine oculis homeobox homolog 1 (SIX1) and contributes to the proliferation and castration resistance of PC. The stabilization of SIX1 by USP1 partially depends on the status of glucose-regulated protein 75 (GRP75). In this study, we aimed to identify a SIX1 degradation inducer via inhibiting the USP1-SIX1 axis. we screened a range of kinase inhibitors and showed that SNS-032 is the best candidate to trigger the ubiquitinated degradation of SIX1. SNS-032 not only restrains activity of the USP1-SIX1 axis and cell cycle progression, but also results in apoptosis of PC cells. Moreover, the combination of SNS-032 and enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis.
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