文献类型：期刊文献

英文题名：RNAi screens identify HES4 as a regulator of redox balance supporting pyrimidine synthesis and tumor growth

作者：He, Jing[1];Wang, Aoxue[2,3];Zhao, Qin[1];Zou, Yejun[2,3,4];Zhang, Zhuo[2,3];Sha, Nannan[1];Hou, Guofang[1];Zhou, Bei[1];Yang, Yi[2];Chen, Tao[5];Zhao, Yuzheng[2,3];Jiang, Yuhui[1]

机构：[1]Shanghai Jiao Tong Univ, Renji Hosp, Dept Liver Surg, Sch Med, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Optogenet & Synthet Biol Interdisciplinary Res Ctr, Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Sch Pharm,State Key Lab Bioreactor Engn, Shanghai, Peoples R China;[3]Chinese Acad Med Sci, Res Unit New Tech Live Cell Metab Imaging, Beijing, Peoples R China;[4]Tongji Univ, Shanghai Matern & Infant Hosp 1, Sch Med, Dept Gynecol, Shanghai, Peoples R China;[5]Tongji Univ, Shanghai East Hosp, Endoscopy Ctr, Sch Med,Dept Gastroenterol, Shanghai, Peoples R China

年份：2024

卷号：31

期号：9

外文期刊名：NATURE STRUCTURAL & MOLECULAR BIOLOGY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001228251000003)】；

基金：This work was supported by the National Key R&D Program of China (2020YFA0803602 to Y.J. and 2019YFA0904800 to Y. Zhao); the National Nature Science Foundation of China (32150030, 32030065, 32121005 and 92049304 to Y. Zhao and 81972586 to Y.J.); the Shanghai Municipal Education Commission (Gaofeng Clinical Medicine grant 20161319 to Y.J.); the Research Unit of New Techniques for Live-Cell Metabolic Imaging (Chinese Academy of Medical Sciences, 2019-I2M-5-013, to Y. Zhao); the Innovative Research Team of High-Level Local Universities in Shanghai; the State Key Laboratory of Bioreactor Engineering; and the Fundamental Research Funds for the Central Universities.

语种：英文

摘要：NADH/NAD+ redox balance is pivotal for cellular metabolism. Systematic identification of NAD(H) redox regulators, although currently lacking, would help uncover unknown effectors critically implicated in the coordination of growth metabolism. In this study, we performed a genome-scale RNA interference (RNAi) screen to globally survey the genes involved in redox modulation and identified the HES family bHLH transcription factor HES4 as a negative regulator of NADH/NAD+ ratio. Functionally, HES4 is shown to be crucial for maintaining mitochondrial electron transport chain (ETC) activity and pyrimidine synthesis. More specifically, HES4 directly represses transcription of SLC44A2 and SDS, thereby inhibiting mitochondrial choline oxidation and cytosolic serine deamination, respectively, which, in turn, ensures coenzyme Q reduction capacity for DHODH-mediated UMP synthesis and serine-derived dTMP production. Accordingly, inhibition of choline oxidation preserves mitochondrial serine catabolism and ETC-coupled redox balance. Furthermore, HES4 protein stability is enhanced under EGFR activation, and increased HES4 levels facilitate EGFR-driven tumor growth and predict poor prognosis of lung adenocarcinoma. These findings illustrate an unidentified mechanism, underlying pyrimidine biosynthesis in the intersection between serine and choline catabolism, and underscore the physiological importance of HES4 in tumor metabolism. The authors identify genes potentially involved in NAD(H) redox modulation and provide insight on major hit HES4, which uses its transcriptional repressive function to drive pyrimidine nucleotide biosynthesis and tumor growth.