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Nat Commun. 2017 Sep 6;8(1):464. doi: 10.1038/s41467-017-00489-5.

Enoyl-CoA hydratase-1 regulates mTOR signaling and apoptosis by sensing nutrients.

Zhang YK1,2,3, Qu YY4,5, Lin Y1,2, Wu XH6, Chen HZ7, Wang X7, Zhou KQ1,2, Wei Y1,2, Guo F1,2, Yao CF1,2, He XD1,2, Liu LX8, Yang C8, Guan ZY9, Wang SD10, Zhao J1,2, Liu DP11, Zhao SM12,13,14, Xu W15,16,17.

Author information

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.
11
State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100010, China. liudp@pumc.edu.cn.
12
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences, Shanghai, 200011, China. zhaosm@fudan.edu.cn.
13
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development, Shanghai, 200433, China. zhaosm@fudan.edu.cn.
14
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. zhaosm@fudan.edu.cn.
15
Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences, Shanghai, 200011, China. xuwei_0706@fudan.edu.cn.
16
Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center for Genetics and Development, Shanghai, 200433, China. xuwei_0706@fudan.edu.cn.
17
State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. xuwei_0706@fudan.edu.cn.

Abstract

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.

PMID:
28878358
PMCID:
PMC5587591
DOI:
10.1038/s41467-017-00489-5
[Indexed for MEDLINE]
Free PMC Article

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