USP11-mediated deubiquitination regulates the protein stability of NR2F1.

The orphan nuclear receptor NR2F1 has been shown to associate with a dormant tumor state in multiple tumor models. However, its dynamic regulation, particularly at the level of protein post-translational modification, remains largely unclear. In this study, we identify the deubiquitinase ubiquitin-specific peptidase 11 (USP11) as a potential regulator that controls the protein stability of NR2F1. USP11 directly interacts with NR2F1, and its overexpression increases NR2F1 protein level by suppressing NR2F1 protein turnover. Mechanistically, USP11 deubiquitinates NR2F1 at K70 and K369 to protect it from proteasomal degradation. Consistent with these findings, USP11 and NR2F1 expression levels are positively correlated across multiple tumor types. Notably, elevated expression of either USP11 or NR2F1 predicts a better prognosis in kidney renal clear cell carcinoma, indicating their potential clinical significance. Together, these findings reveal a post-translational regulatory mechanism of NR2F1 and suggest that targeting USP11 may provide a potential strategy for modulating tumor dormancy.