Department of Life Sciences, Sogang University, Seoul 04107, Korea.
Int J Mol Sci. 2021 Feb 16;22(4):1936. doi: 10.3390/ijms22041936.
Aurora kinases are serine/threonine kinases required for cell proliferation and are overexpressed in many human cancers. Targeting Aurora kinases has been a therapeutic strategy in cancer treatment. Here, we attempted to identify a deubiquitinase (DUB) that regulates Aurora kinase A (Aurora-A) protein stability and/or kinase activity as a potential cancer therapeutic target. Through pull-down assays with the human DUB library, we identified OTUD6A as an Aurora-A-specific DUB. OTUD6A interacts with Aurora-A through OTU and kinase domains, respectively, and deubiquitinates Aurora-A. Notably, OTUD6A promotes the protein half-life of Aurora-A and activates Aurora-A by increasing phosphorylation at threonine 288 of Aurora-A. From qPCR screening, we identified and validated that the cancer gene encoding Cyclin-dependent kinases regulatory subunit 2 is the most upregulated cell cycle regulator when OTUD6A is overexpressed. The results suggest that OTUD6A may serve as a therapeutic target in human cancers.
极光激酶是细胞增殖所必需的丝氨酸/苏氨酸激酶，在许多人类癌症中过度表达。靶向极光激酶已成为癌症治疗的一种治疗策略。在这里，我们试图鉴定一种去泛素化酶（DUB），作为潜在的癌症治疗靶点，调节极光激酶 A（极光-A）蛋白稳定性和/或激酶活性。通过使用人 DUB 文库进行下拉测定，我们鉴定出 OTUD6A 是一种极光-A 特异性 DUB。OTUD6A 通过 OTU 和激酶结构域分别与极光-A 相互作用，并对极光-A 进行去泛素化。值得注意的是，OTUD6A 通过增加极光-A 丝氨酸 288 的磷酸化来促进极光-A 的蛋白半衰期并激活极光-A。通过 qPCR 筛选，我们发现并验证了当 OTUD6A 过表达时，编码细胞周期蛋白依赖性激酶调节亚基 2 的致癌基因是上调最明显的细胞周期调节剂。结果表明，OTUD6A 可能是人类癌症的治疗靶点。
