The neddylation-cullin 2-RBX1 E3 ligase axis targets tumor suppressor RhoB for degradation in liver cancer.

The neddylation-cullin-RING E3 ligase (CRL) pathway has recently been identified as a potential oncogenic event and attractive anticancer target; however, its underlying mechanisms have not been well elucidated. In this study, RhoB, a well known tumor suppressor, was identified and validated with an iTRAQ-based quantitative proteomic approach as a new target of this pathway in liver cancer cells. Specifically, cullin 2-RBX1 E3 ligase, which requires NEDD8 conjugation for its activation, interacted with RhoB and promoted its ubiquitination and degradation. In human liver cancer tissues, the neddylation-CRL pathway was overactivated and reversely correlated with RhoB levels. Moreover, RhoB accumulation upon inhibition of the neddylation-CRL pathway for anticancer therapy contributed to the induction of tumor suppressors p21 and p27, apoptosis, and growth suppression. Our findings highlight the degradation of RhoB via the neddylation-CRL pathway as an important molecular event that drives liver carcinogenesis and RhoB itself as a pivotal effector for anticancer therapy targeting this oncogenic pathway.