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.