Abstract：
Cell division cycle 123 (CDC123) has been implicated in a variety of human diseases. However, it remains unclear whether CDC123 plays a role in tumorigenesis and how its abundance is regulated. In this study, we found that CDC123 was highly expressed in breast cancer cells, and its high expression was positively correlated with a poor prognosis. Knowndown of CDC123 impaired the proliferation of breast cancer cells. Mechanistically, we identified a deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), that could physically interact with and deubiquitinate K48-linked ubiquitinated CDC123 at the K308 site. Therefore, the expression of CDC123 was positively correlated with USP9X in breast cancer cells. In addition, we found that deletion of either USP9X or CDC123 led to altered expression of cell cycle-related genes and resulted in the accumulation of cells population in the G0/G1 phase, thereby suppressing cell proliferation. Treatment with the deubiquitinase inhibitor of USP9X, WP1130 (Degrasyn, a small molecule compound that USP9X deubiquitinase inhibitor), also led to the accumulation of breast cancer cells in the G0/G1 phase, but this effect could be rescued by overexpression of CDC123. Furthermore, our study revealed that the USP9X/CDC123 axis promotes the occurrence and development of breast cancer through regulating the cell cycle, and suggests that it may be a potential target for breast cancer intervention. In conclusion, our study demonstrates that USP9X is a key regulator of CDC123, providing a novel pathway for the maintenance of CDC123 abundance in cells, and supports USP9X/CDC123 as a potential target for breast cancer intervention through regulating the cell cycle.
摘要：
细胞分裂周期123(CDC123)与多种人类疾病有关。然而,目前尚不清楚CDC123是否在肿瘤发生中发挥作用,以及其丰度如何受到调控.在这项研究中,我们发现CDC123在乳腺癌细胞中高表达，高表达与不良预后呈正相关。了解CDC123会损害乳腺癌细胞的增殖。机械上,我们发现了一种去泛素酶,泛素特异性肽酶9，X连接（USP9X），可以在K308位点与K48连接的泛素化CDC123物理相互作用并去泛素化。因此,CDC123与USP9X在乳腺癌细胞中的表达呈正相关。此外,我们发现，USP9X或CDC123的缺失导致细胞周期相关基因的表达改变，并导致G0/G1期细胞群体的积累，从而抑制细胞增殖。用USP9X去泛素酶抑制剂治疗，WP1130(Degrasyn,USP9X去泛素酶抑制剂的小分子化合物），也导致乳腺癌细胞在G0/G1期的积累，但是这种作用可以通过CDC123的过表达来挽救。此外，研究发现USP9X/CDC123轴通过调节细胞周期促进乳腺癌的发生发展,并表明它可能是乳腺癌干预的潜在目标。总之,我们的研究表明，USP9X是CDC123的关键调节因子，为维持细胞中CDC123的丰度提供了新的途径，并支持USP9X/CDC123通过调节细胞周期作为乳腺癌干预的潜在靶点。
