Yan Tingmang, Zhou Dapeng, Shi Youwei, Cui Di, Jiang Juntao, Han Bangmin, Xia Shujie, Wang Zhou, Liu Haitao, Guo Wenhuan, Jing Yifeng
Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Front Oncol. 2021 Apr 16;11:637040. doi: 10.3389/fonc.2021.637040. eCollection 2021.
Siah2 is an E3 ubiquitin ligase that targets androgen receptor (AR) and plays an important role in the development of castration-resistant prostate cancer (CRPC). However, the regulation of Siah2 in prostate cancer (PCa) is largely unknown. In this study, we used AR-dependent and -independent cells lines to investigate the cellular roles of AR and androgen deprivation therapy (ADT) on Siah2 protein levels and E3 ligase activity using Western blotting and co-immunoprecipitation. We also validated our findings using patient samples taken before and after ADT. Finally, we used xenograft tumor models to test the effects of ADT combined with vitamin K3 (Vit K3) on tumor growth . Our results showed that AR stabilizes Siah2 protein by attenuating its self-ubiquitination and auto-degradation, likely by blocking its E3 ubiquitin ligase activity. Conversely, ADT decreased Siah2 protein expression but enhanced its E3 ligase activity in PCa cells. Notably, the findings that ADT decreasing Siah2 protein expression were verified in a series of paired PCa samples from the same patient. Additionally, we found that ADT-induced Siah2 activation could be abolished by Vit K3. Strikingly, ADT combined with Vit K3 treatment delayed the occurrence of CRPC and dramatically inhibited the growth of tumor xenografts compared with ADT treatment alone. AR is an inhibitor of Siah2 in PCa, and ADT leads to the continuous activation of Siah2, which may contribute to CRPC. Finally, ADT+Vit K3 may be a potential approach to delay the occurrence of CRPC.
Siah2是一种靶向雄激素受体（AR）的E3泛素连接酶，在去势抵抗性前列腺癌（CRPC）的发展中起重要作用。然而，Siah2在前列腺癌（PCa）中的调控机制在很大程度上尚不清楚。在本研究中，我们使用依赖AR和不依赖AR的细胞系，通过蛋白质免疫印迹法和免疫共沉淀法，研究AR和雄激素剥夺疗法（ADT）对Siah2蛋白水平和E3连接酶活性的细胞作用。我们还使用ADT前后采集的患者样本验证了我们的发现。最后，我们使用异种移植肿瘤模型来测试ADT联合维生素K3（Vit K3）对肿瘤生长的影响。我们的结果表明，AR可能通过阻断其E3泛素连接酶活性，减弱Siah2的自身泛素化和自动降解，从而稳定Siah2蛋白。相反，ADT降低了PCa细胞中Siah2蛋白的表达，但增强了其E3连接酶活性。值得注意的是，ADT降低Siah2蛋白表达这一发现，在同一患者的一系列配对PCa样本中得到了验证。此外，我们发现Vit K3可以消除ADT诱导的Siah2激活。令人惊讶的是，与单独使用ADT治疗相比，ADT联合Vit K3治疗延迟了CRPC的发生，并显著抑制了肿瘤异种移植的生长。在PCa中，AR是Siah2的抑制剂，ADT导致Siah2持续激活，这可能促成CRPC。最后，ADT + Vit K3可能是一种延缓CRPC发生的潜在方法。
