Department of Urology, National Cancer Center, National Clinical Research Center For Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Cancer Lett. 2019 Aug 1;456:49-58. doi: 10.1016/j.canlet.2019.04.020. Epub 2019 Apr 17.
The zinc metalloprotease STAM-binding protein-like 1 (STAMBPL1) has been identified as a deubiquitinase by specifically cleaving Lys-63-linked polyubiquitin chains, but its cellular function remains unclear. Here we described the potential role of STAMBPL1 in suppression of the intrinsic apoptosis. We observed substantially high amounts of STAMBPL1 proteins in androgen-independent prostate cancer PC3 and DU145 cell lines. STAMBPL1 RNAi depletion triggered caspase-3/-7-dependent apoptosis in PC3 and DU145 cells. STAMBPL1 knockdown-induced apoptosis was accompanied by accumulation of cellular ROS and a decrease in endogenous caspase inhibitor XIAP protein content. Treatment cells with antioxidant NAC delayed STAMBPL1 silencing-induced apoptosis, whereas ectopic expression of XIAP almost completely abrogated apoptosis. We further elucidated that STAMBPL1 knockdown diverted XIAP protein to lysosomal degradation pathway. Taken together, these studies show that STAMBPL1 depletion induces apoptosis by promoting XIAP lysosomal degradation, and suggest that targeting deubiquitinase STAMBPL1 might offer promising therapeutic strategy for prostate cancer.
锌金属蛋白酶 STAM 结合蛋白样 1（STAMBPL1）已被鉴定为一种去泛素化酶，能够特异性切割 Lys-63 连接的多泛素链，但它的细胞功能仍不清楚。在这里，我们描述了 STAMBPL1 在抑制内在细胞凋亡中的潜在作用。我们观察到雄激素非依赖性前列腺癌 PC3 和 DU145 细胞系中 STAMBPL1 蛋白的含量相当高。STAMBPL1 RNAi 耗竭可触发 PC3 和 DU145 细胞中 caspase-3/-7 依赖性凋亡。STAMBPL1 敲低诱导的细胞凋亡伴随着细胞内 ROS 的积累和内源性 caspase 抑制剂 XIAP 蛋白含量的减少。用抗氧化剂 NAC 处理细胞可延迟 STAMBPL1 沉默诱导的细胞凋亡，而 XIAP 的异位表达几乎完全阻断了细胞凋亡。我们进一步阐明，STAMBPL1 敲低将 XIAP 蛋白转向溶酶体降解途径。总之，这些研究表明，STAMBPL1 耗竭通过促进 XIAP 的溶酶体降解诱导细胞凋亡，并表明靶向去泛素化酶 STAMBPL1 可能为前列腺癌提供有前途的治疗策略。
