机构：[1]Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences, Shanghai 200011, China.[2]Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development, Shanghai 200433, China.[3]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[4]Department of Urology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.[5]Department of Oncology, Shanghai Medical College, Shanghai 200032, China.[6]Institute of Developmental Biology and Molecular Medicine, Fudan University, Shanghai 200032, China.[7]State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100010, China.[8]Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.[9]Sophie Davis School of Biomedical Education, City University of New York Medical School, New York, NY 10031, USA.[10]Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
The oncogenic mechanisms of overnutrition, a confirmed independent cancer risk factor, remain poorly understood. Herein, we report that enoyl-CoA hydratase-1 (ECHS1), the enzyme involved in the oxidation of fatty acids (FAs) and branched-chain amino acids (BCAAs), senses nutrients and promotes mTOR activation and apoptotic resistance. Nutrients-promoted acetylation of lys101 of ECHS1 impedes ECHS1 activity by impairing enoyl-CoA binding, promoting ECHS1 degradation and blocking its mitochondrial translocation through inducing ubiquitination. As a result, nutrients induce the accumulation of BCAAs and FAs that activate mTOR signaling and stimulate apoptosis, respectively. The latter was overcome by selection of BCL-2 overexpressing cells under overnutrition conditions. The oncogenic effects of nutrients were reversed by SIRT3, which deacetylates lys101 acetylation. Severely decreased ECHS1, accumulation of BCAAs and FAs, activation of mTOR and overexpression of BCL-2 were observed in cancer tissues from metabolic organs. Our results identified ECHS1, a nutrients-sensing protein that transforms nutrient signals into oncogenic signals.Overnutrition has been linked to increased risk of cancer. Here, the authors show that exceeding nutrients suppress Enoyl-CoA hydratase-1 (ECHS1) activity by inducing its acetylation resulting in accumulation of fatty acids and branched-chain amino acids and oncogenic mTOR activation.
基金：
State Key Development Programs (973) of Basic Research of China [2013CB531200, 2013CB945100, 2013CB911204, 2015AA020913]; National Science Foundation of ChinaNational Natural Science Foundation of China [31330023, 81301717, 81471454]; Science and Technology Municipal Commission of Shanghai [16JC1405300, 14ZR1402000, 12ZR1440800]; [2014DFA30630]
语种：
外文
WOS：
PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
最新[2023]版：
大类|1 区综合性期刊
小类|1 区综合性期刊
第一作者：
第一作者机构：[1]Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences, Shanghai 200011, China.[2]Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development, Shanghai 200433, China.[3]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
共同第一作者：
通讯作者：
通讯机构：[1]Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences, Shanghai 200011, China.[2]Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development, Shanghai 200433, China.[3]State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.[7]State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100010, China.
推荐引用方式(GB/T 7714)：
Zhang Ya-Kun,Qu Yuan-Yuan,Lin Yan,et al.Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.[J].Nature communications.2017,8(1):464.doi:10.1038/s41467-017-00489-5.
APA：
Zhang Ya-Kun,Qu Yuan-Yuan,Lin Yan,Wu Xiao-Hui,Chen Hou-Zao...&Xu Wei.(2017).Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients..Nature communications,8,(1)
MLA：
Zhang Ya-Kun,et al."Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.".Nature communications 8..1(2017):464
综合性期刊