The epithelial-mesenchymal transition (EMT) represents a cellular de-differentiation process that provides cells with the increased plasticity required during embryonic development, tissue remodeling, wound healing and
metastasis. Slug and Twist are two key EMT
transcription factors (EMT-TFs) that are tightly regulated via ubiquitination and degradation. How Slug and Twist escape degradation and become stabilized in
cancer cells remains unclear. One plausible mechanism of Slug and Twist stabilization involves removal of
ubiquitin by
deubiquitinases (DUBs). In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and
Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their
protein levels. Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of
breast cancer cells. Intriguingly, Dub3 was identified as an early response gene that was upregulated after exposure to inflammatory
cytokines such as
IL-6, which plays a critical role in the growth and
metastasis of
breast cancer cells, as well as the maintenance of breast CSCs. We found that Dub3 played an essential role in
IL-6 induced EMT through stabilization of Slug and Twist. Our study has uncovered an IL-6-Dub3-Slug/Twist signaling axis during EMT and suggests potential approaches that could target Dub3 to prevent metastatic
breast tumor.