Lysine Acetylation Activates 6-Phosphogluconate Dehydrogenase to Promote Tumor Growth

• Type of Material: Article
• Authors: Changliang Shan, Emory University; Shannon Elf, Emory University; Quanjian Ji, University of Chicago; Hee-Bum Kang, Emory University; Lu Zhou, University of Chicago; Taro Hitosugi, Emory University; Lingtao Jin, Emory University; Ruiting Lin, Emory University; Liang Zhang, University of Chicago; Jae Ho Seo, Emory University; Jianxin Xie, Cell Signaling Technology, Inc.; Meghan Tucker, Cell Signaling Technology, Inc.; Ting-Lei Gu, Cell Signaling Technology, Inc.; Jessica Sudderth, University of Texas Southwestern; Lei Jiang, University of Texas Southwestern; Ralph J. DeBerardinis, University of Texas Southwestern; Shaoxiong Wu, Emory University; Yuancheng Li, Emory University; Hui Mao, Emory University; Peng Chen, Peking University; Dongsheng Wang, Emory University; Georgia Chen, Emory University; Sagar Lonial, Emory University; Martha Arellano, Emory University; Hanna Khoury, Emory University; Fadlo Khuri, Emory University; Benjamin H. Lee, Novartis Institutes for BioMedical Research; Daniel Brat, Emory University; Keqiang Ye, Emory University; Titus J. Boggon, Yale University; Chuan He, University of Chicago; Sumin Kang, Emory University; Jun Fan, Emory University; Jing Chen, Emory University
• Language: English
• Date: 2014-08-21
• Publisher: Elsevier (Cell Press): 12 month embargo
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.molcel.2014.06.020
• Title of Journal or Parent Work: Molecular Cell
• ISSN: 1097-2765
• Volume: 55
• Issue: 4
• Start Page: 552
• End Page: 565
• Grant/Funding Information: This work was supported in part by NIH grants CA140515, CA183594, CA174786 (J.C.), CA175316 (S.K.), GM071440 (C.H.) and the Pharmacological Sciences Training Grant T32 GM008602 (S.E.), DoD grant W81XWH-12-1-0217 (J.C.), National Natural Science Funds of China No.20902013 (L.Z.), Charles Harris Run For Leukemia, Inc. (H.J.K.) and the Hematology Tissue Bank of the Emory University School of Medicine and the Georgia Cancer Coalition (H.J.K.).
• Keywords: Science & Technology; Cell Biology; TYROSINE PHOSPHORYLATION; METABOLISM; Life Sciences & Biomedicine; Biochemistry & Molecular Biology
• Research Categories: Biology, Cell; Biology, Molecular

Abstract

Although the oxidative pentose phosphate pathway is important for tumor growth, how 6-phosphogluconate dehydrogenase (6PGD) in this pathway is upregulated in human cancers is unknown. We found that 6PGD is commonly activated in EGF-stimulated cells and human cancer cells by lysine acetylation. Acetylation at K76 and K294 of 6PGD promotes NADP+ binding to 6PGD and formation of active 6PGD dimers, respectively. Moreover, we identified DLAT and ACAT2 as upstream acetyltransferases of K76 and K294, respectively, and HDAC4 as the deacetylase of both sites. Expressing acetyl-deficient mutants of 6PGD in cancer cells significantly attenuated cell proliferation and tumor growth. This is due in partto reduced levels of 6PGD products ribulose-5-phosphate and NADPH, which led to reduced RNA and lipid biosynthesis as well as elevated ROS. Furthermore, 6PGD activity is upregulated with increased lysine acetylation in primary leukemia cells from human patients, providing mechanistic insights into 6PGD upregulation in cancer cells.