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

Ya-Kun Zhang, Yuan-Yuan Qu, Yan Lin, Xiao-Hui Wu, Hou-Zao Chen, Xu Wang, Kai-Qiang Zhou, Yun Wei, Fushen Guo, Cui-Fang Yao, Xia-Di He, Li-Xia Liu, Chen Yang, Zong-Yuan Guan, Shi-Dong Wang, Jianyuan Zhao, Liu De-Pei (), Shi-Min Zhao () and Wei Xu ()
Additional contact information
Ya-Kun Zhang: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Yuan-Yuan Qu: Fudan University Shanghai Cancer Center
Yan Lin: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Xiao-Hui Wu: Fudan University
Hou-Zao Chen: Chinese Academy of Medical Sciences & Peking Union Medical College
Xu Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Kai-Qiang Zhou: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Yun Wei: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Fushen Guo: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Cui-Fang Yao: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Xia-Di He: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Li-Xia Liu: Chinese Academy of Sciences
Chen Yang: Chinese Academy of Sciences
Zong-Yuan Guan: City University of New York Medical School
Shi-Dong Wang: Vanderbilt University School of Medicine
Jianyuan Zhao: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Liu De-Pei: Chinese Academy of Medical Sciences & Peking Union Medical College
Shi-Min Zhao: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences
Wei Xu: Obstetrics & Gynecology Hospital of Fudan University, State Key Lab of Genetic Engineering, Institutes of Biomedical Sciences and School of Life Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00489-5

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