Xu Junfeng, Li Lihui, Yu Guangyang, Ying Wantao, Gao Qiang, Zhang Wenjuan, Li Xianyu, Ding Chen, Jiang Yanan, Wei Dongping, Duan Shengzhong, Lei Qunying, Li Peng, Shi Tieliu, Qian Xiaohong, Qin Jun, Jia Lijun
From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and ¶Institutes of Biomedical Sciences, Shanghai Medical College, and.
From the ‡Cancer Institute, Fudan University Shanghai Cancer Center, §Department of Oncology and.
Mol Cell Proteomics. 2015 Mar;14(3):499-509. doi: 10.1074/mcp.M114.045211. Epub 2014 Dec 24.
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.
NEDD8化-库林-RING E3连接酶（CRL）途径最近被确定为一种潜在的致癌事件和有吸引力的抗癌靶点；然而，其潜在机制尚未得到充分阐明。在本研究中，通过基于iTRAQ的定量蛋白质组学方法鉴定并验证了著名的肿瘤抑制因子RhoB是肝癌细胞中该途径的一个新靶点。具体而言，需要NEDD8缀合以激活的库林2-RBX1 E3连接酶与RhoB相互作用，并促进其泛素化和降解。在人类肝癌组织中，NEDD8化-CRL途径过度激活，且与RhoB水平呈负相关。此外，在抑制NEDD8化-CRL途径进行抗癌治疗时RhoB的积累有助于诱导肿瘤抑制因子p21和p27、促进细胞凋亡以及抑制生长。我们的研究结果突出了通过NEDD8化-CRL途径降解RhoB是驱动肝癌发生的一个重要分子事件，以及RhoB本身是针对这一致癌途径进行抗癌治疗的关键效应分子。
