ASB3 knockdown promotes mitochondrial apoptosis via activating the interdependent cleavage of Beclin1 and caspase-8 in hepatocellular carcinoma

作     者：Wenli Zhang Fuchen Liu Zhihui Che Mengmeng Wu Zihui Tang Jie Liu Dongqin Yang 

作者机构：Department of Digestive Diseases of Huashan HospitalFudan UniversityShanghai 200040China The Third Department of Hepatic SurgeryEastern Hepatobiliary Surgery HospitalSecond Military Medical UniversityShanghai 200438China 

出 版 物：《Science China(Life Sciences)》 (中国科学（生命科学英文版）)

年 卷 期：2019年第62卷第12期

页      面：1692-1702页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China (81372652, 81772529 and 81770579) the Development Fund for Shanghai Talents (201660) 

主　　题：ASB3 apoptosis Beclin1 caspase-8 autophagy liver cancer 

摘      要：Apoptosis and autophagy are distinct cellular processes that can be highly interconnected. The cross talk between the two processes is indispensable in determining the overall cell fate. Although the apoptosis-promoting effect of caspases has been demonstrated, the roles of autophagy-related proteins and even autophagy itself in regulating apoptosis remain poorly understood. In our present study, we found that downregulation of ubiquitin E3 ligase ASB3 led to enhanced mitochondrial apoptosis as well as autophagy, which synergistically promoted cell death in hepatocellular carcinoma(HCC). We observed the activation of caspase-8 and decrease of autophagy protein Beclin1 in apoptotic cells that were depleted of ASB3. Beclin1 was mainly cleaved by activated caspase-8 and active Beclin1 initiated mitochondrial apoptosis via locating its C-terminal fragment to mitochondria. In addition, knocking down of Beclin1 markedly blocked the apoptosis, indicating its essential role in the ***, our study indicated that enhanced autophagy level might be involved in the activation of caspase-8 and promote the apoptosis. Taken together, our results demonstrated that ASB3 can regulate mitochondrial pathway of apoptosis by controlling caspase-8 mediated cleavage of Beclin1 in HCC. Therefore, ASB3 may potentially serve as a novel target for HCC therapy,especially when combined with autophagy agonist.