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

• Published in: Nature communications Vol. 8; no. 1; pp. 464 - 16
• Main Authors: Zhang, Ya-Kun, Qu, Yuan-Yuan, Lin, Yan, Wu, Xiao-Hui, Chen, Hou-Zao, Wang, Xu, Zhou, Kai-Qiang, Wei, Yun, Guo, Fushen, Yao, Cui-Fang, He, Xia-Di, Liu, Li-Xia, Yang, Chen, Guan, Zong-Yuan, Wang, Shi-Dong, Zhao, Jianyuan, Liu, De-Pei, Zhao, Shi-Min, Xu, Wei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/458/1275; 631/67/2327; 631/80/86/2369; Acetylation; Amino acids; Amino Acids, Branched-Chain - metabolism; Animals; Apoptosis; Cancer; Carcinogenesis; Cell Line, Tumor; Chain branching; Enoyl-CoA hydratase; Enoyl-CoA Hydratase - metabolism; Fatty acids; Gene Expression Regulation, Neoplastic; HCT116 Cells; Health risks; HEK293 Cells; Hep G2 Cells; Humanities and Social Sciences; Humans; Lysine - chemistry; Male; Mice; Mice, Knockout; multidisciplinary; Neoplasm Transplantation; Nutrients; Overnutrition; Recombinant Proteins - chemistry; Risk factors; Science; Science (multidisciplinary); Signal Transduction; Sirtuin 3 - metabolism; TOR protein; TOR Serine-Threonine Kinases - metabolism; Translocation; Ubiquitin - chemistry
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00489-5

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 lys 101 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 lys 101 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.