Graduate School of Biomedical Science and Engineering, Department of Biomedical Science, Hanyang University, 222 Wangsimni-ro, Seongdong, Seoul 04763, South Korea.
Graduate School of Biomedical Science and Engineering, Department of Biomedical Science, Hanyang University, 222 Wangsimni-ro, Seongdong, Seoul 04763, South Korea; College of Medicine, Hanyang University, Seoul 04763, South Korea.
Mol Ther. 2022 Nov 2;30(11):3414-3429. doi: 10.1016/j.ymthe.2022.07.019. Epub 2022 Aug 1.
Survivin is a component of the chromosomal passenger complex, which includes Aurora B, INCENP, and Borealin, and is required for chromosome segregation and cytokinesis. We performed a genome-wide screen of deubiquitinating enzymes for survivin. For the first time, we report that USP19 has a dual role in the modulation of mitosis and tumorigenesis by regulating survivin expression. Our results found that USP19 stabilizes and interacts with survivin in HCT116 cells. USP19 deubiquitinates survivin protein and extends its half-life. We also found that USP19 functions as a mitotic regulator by controlling the downstream signaling of survivin protein. Targeted genome knockout verified that USP19 depletion leads to several mitotic defects, including cytokinesis failure. In addition, USP19 depletion results in significant enrichment of apoptosis and reduces the growth of tumors in the mouse xenograft. We envision that simultaneous targeting of USP19 and survivin in oncologic drug development would increase therapeutic value and minimize redundancy.
Survivin 是染色体乘客复合物的一个组成部分，该复合物包括 Aurora B、INCENP 和 Borealin，是染色体分离和胞质分裂所必需的。我们对去泛素化酶进行了全基因组筛选，以寻找 survivin。我们首次报道 USP19 通过调节 survivin 的表达在有丝分裂和肿瘤发生中具有双重作用。我们的结果发现，USP19 在 HCT116 细胞中稳定和与 survivin 相互作用。USP19 去泛素化 survivin 蛋白并延长其半衰期。我们还发现，USP19 通过控制 survivin 蛋白的下游信号转导作为有丝分裂调节剂发挥作用。靶向基因组敲除证实，USP19 耗竭导致有丝分裂缺陷，包括胞质分裂失败。此外，USP19 耗竭导致凋亡明显富集，并减少小鼠异种移植肿瘤的生长。我们设想，在肿瘤药物开发中同时靶向 USP19 和 survivin 将增加治疗价值并最小化冗余。
