Shao Zhenlong, Liu Shutong, Sun Wenshuang, Zhuang Xuefen, Yin Shusha, Cheng Ji, Xia Xiaohong, Liao Yuning, Liu Jinbao, Huang Hongbiao
Guangzhou Institute of Cancer Research, The Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, 510095, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
Cell Mol Biol Lett. 2024 Dec 2;29(1):146. doi: 10.1186/s11658-024-00665-8.
Sentrin/SUMO-specific protease 3 (SENP3) is essential to regulate protein stability and function in normal and cancer cells. Nevertheless, its role and action mechanisms in prostate cancer (PCa) remain elusive. Thus, clarification of SENP3's involvement and the SUMOylation process in PCa is pivotal for discovering potential targets and understanding SUMOylation dynamics.
Cell viability, EdU staining, live cell imaging, and cell cycle assays were used to determine proliferation of PCa cells. Transwell and wound-healing assays were used to detect migration of PCa cells. The interaction between SENP3 and SIX1 was determined by co-immunoprecipitation, western blotting, and immunofluorescence assays. Xenograft models established on NOD-SCID mice were used to evaluate in vivo effects post SENP3 knockdown. Immunohistochemistry was performed to investigate the expression of SENP3 in PCa tissues.
This study found that SENP3 is highly expressed in PCa cell lines and tissues from PCa patients. Overexpressed SENP3 is associated with metastatic malignancy in PCa. Various in vivo and in vitro experiments confirmed that SENP3 promotes the proliferation and migration of PCa. In addition, SENP3 interacts with the SD domain of SIX1 and mediates its deSUMOylation and protein stability. Lys154 (K154) is required for the SUMOylation of SIX1. More importantly, SENP3 promotes the malignancy of PCa through the regulation of SIX1.
We unravel the significant role of SENP3 in regulating protein stability of SIX1 and progression of PCa, which may deepen our understanding of the SUMOylation modification and provide a promising target for management of metastatic PCa.
Sentrin/SUMO特异性蛋白酶3（SENP3）对于调节正常细胞和癌细胞中的蛋白质稳定性及功能至关重要。然而，其在前列腺癌（PCa）中的作用及作用机制仍不清楚。因此，阐明SENP3在PCa中的参与情况及SUMO化过程对于发现潜在靶点和理解SUMO化动态变化至关重要。
采用细胞活力、EdU染色、活细胞成像和细胞周期分析来确定PCa细胞的增殖情况。采用Transwell和伤口愈合分析来检测PCa细胞的迁移情况。通过免疫共沉淀、蛋白质印迹和免疫荧光分析来确定SENP3与SIX1之间的相互作用。利用在NOD-SCID小鼠上建立的异种移植模型来评估SENP3敲低后的体内效应。进行免疫组织化学以研究SENP3在PCa组织中的表达。
本研究发现SENP3在PCa细胞系和PCa患者的组织中高表达。SENP3过表达与PCa的转移性恶性肿瘤相关。各种体内和体外实验证实SENP3促进PCa的增殖和迁移。此外，SENP3与SIX1的SD结构域相互作用并介导其去SUMO化和蛋白质稳定性。SIX1的SUMO化需要赖氨酸154（K154）。更重要的是，SENP3通过调节SIX1促进PCa的恶性发展。
我们揭示了SENP3在调节SIX1的蛋白质稳定性和PCa进展中的重要作用，这可能加深我们对SUMO化修饰的理解，并为转移性PCa的治疗提供一个有前景的靶点。
